O-linked pyrimidin-4-amine-based compounds, compositions comprising them, and methods of their use to treat cancer

ABSTRACT

O-linked pyrimidin-4-amine-based compounds, pharmaceutical compositions comprising them, and methods of their use are described. Particular compounds of the invention are of formula I:

This application claims priority to U.S. provisional application No.60/874,882, filed Dec. 14, 2006, the entirety of which is incorporatedherein by reference.

1. FIELD OF THE INVENTION

This invention relates to O-linked pyrimidin-4-amine-based compounds,pharmaceutical compositions comprising them, and methods of their use totreat, manage and prevent cancer.

2. BACKGROUND OF THE INVENTION

Deoxycytidine kinase is an enzyme involved in deoxynucleoside salvage,supplying precursors for DNA synthesis. Csapó, Z. et al., ActaBiochimica Polonica 48(1):251-256, 251 (2001). The enzyme is able tophosphorylate three of the four deoxynucleosides, and alsophosphorylates a variety of antineoplastic and antiviral nucleosideanalogues. Id.; Chottiner, E. G., et al, Proc. Natl. Acad. Sci. USA88:1531-1535, 1531 (1991). For example, the enzyme reportedly activatescytosineb-D-arabinofuranoside (AraC), fludarabine and cladribine, thechemotherapeutic agents gemcytabine and troxacitabine, and theantivirals 3TC and ddC, which are used in the treatment of HIVinfection. Sabini, E. et al., Nature Stuct. Biol. 10(7):513-519, 513(2003).

Although deoxycytidine kinase activates some anti-cancer drugs, reportssuggest that at least one anti-cancer drug may act, at least in part, byinhibiting the enzyme. See, e.g., International Application WO04/103374.In this regard, a link between neoplastic transformation and increaseddeoxycytidine kinase levels in solid cancer tissues has been reported.See Arnér, E. S. J. and Eriksson, S., Pharmac. Ther. 67(2):155-186, 165(1995). Some deoxycytidine kinase inhibitors have been reported. See,e.g., Krenitsky, T. A. et al., J. Biol. Chem. 251(13):4055-4061 (1976);Ward, A. D. and Baker, B. R., J. Med. Chem. 20(1):88-92 (1976).

3. SUMMARY OF THE INVENTION

This invention encompasses O-linked pyrimidin-4-amine-based compounds,pharmaceutical compositions comprising them, and methods of their use.

Embodiments of the invention encompasses compounds of formulae I, II andIII:

and pharmaceutically acceptable salts and solvates thereof, the varioussubstituents of which are defined here. Particular compounds are potentdeoxycytidine kinase inhibitors.

The invention encompasses pharmaceutical formulations and single unitdosage forms comprising compounds disclosed here.

The invention also encompasses methods of inhibiting deoxycytidinekinase, and methods of treating, managing and preventing diseases anddisorders, such as cancer.

4. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the effect of a compound of the invention alone, and incombination with 4-hydroperoxycyclophosphamide (4-HC), on the growth ofmouse B cell lymphoma cells (BCL-1). The effect is shown as a percentageof the control rate of growth (i.e., untreated BCL-1 cells). Here, theconcentration of the compound was 1 μM, and the concentration of 4-HC(when used) is shown in the x-axis.

FIG. 2 shows the effect of 3 μM of the compound alone, and incombination with 4-HC, on BCL-1 cell growth.

FIG. 3 shows the effect of 10 μM of the compound alone, and incombination with 4-HC, on BCL-1 cell growth.

FIG. 4 shows the effect of 20 μM of the compound alone, and incombination with 4-HC, on BCL-1 cell growth.

5. DETAILED DESCRIPTION OF THE INVENTION

This invention is directed, in part, to O-linked pyrimidin-4-amine-basedcompounds and compositions comprising them. Particular compounds of theinvention inhibit deoxycytidine kinase, and may be useful in thetreatment of cancer.

5.1. Definitions

Unless otherwise indicated, the term “alkenyl” means a straight chain,branched and/or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 10 or2 to 6) carbon atoms, and including at least one carbon-carbon doublebond. Representative alkenyl moieties include vinyl, allyl, 1-butenyl,2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl and3-decenyl.

Unless otherwise indicated, the term “alkoxy” means an —O-alkyl group.Examples of alkoxy groups include, but are not limited to, —OCH₃,—OCH₂CH₃, —O(CH₂)₂CH₃, —O(CH₂)₃CH₃, —O(CH₂)₄—CH₃, and —O(CH₂)₅CH₃. Theterm “lower alkoxy” refers to —O-(lower alkyl).

Unless otherwise indicated, the term “alkyl” means a straight chain,branched and/or cyclic (“cycloalkyl”) hydrocarbon having from 1 to 20(e.g., 1 to 10 or 1 to 4) carbon atoms. Alkyl moieties having from 1 to4 carbons are referred to as “lower alkyl.” Examples of alkyl groupsinclude methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. Cycloalkylmoieties may be monocyclic or multicyclic, and examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl.Additional examples of alkyl moieties have linear, branched and/orcyclic portions (e.g., 1-ethyl-4-methyl-cyclohexyl). The term “alkyl”includes saturated hydrocarbons as well as alkenyl and alkynyl moieties.

Unless otherwise indicated, the term “alkylaryl” or “alkyl-aryl” meansan alkyl moiety bound to an aryl moiety.

Unless otherwise indicated, the term “alkylheteroaryl” or“alkyl-heteroaryl” means an alkyl moiety bound to a heteroaryl moiety.

Unless otherwise indicated, the term “alkylheterocycle” or“alkyl-heterocycle” means an alkyl moiety bound to a heterocycle moiety.

Unless otherwise indicated, the term “alkynyl” means a straight chain,branched or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 6) carbonatoms, and including at least one carbon-carbon triple bond.Representative alkynyl moieties include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl,1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl,1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl,1-decynyl, 2-decynyl and 9-decynyl.

Unless otherwise indicated, the term “aryl” means an aromatic ring or anaromatic or partially aromatic ring system composed of carbon andhydrogen atoms. An aryl moiety may comprise multiple rings bound orfused together. Examples of aryl moieties include anthracenyl, azulenyl,biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, phenyl,1,2,3,4-tetrahydro-naphthalene, and tolyl.

Unless otherwise indicated, the term “arylalkyl” or “aryl-alkyl” meansan aryl moiety bound to an alkyl moiety.

Unless otherwise indicated, the term “dCK_IC₅₀” means an IC₅₀ for humanrecombinant deoxycytidine kinase as determined using the filter bindingassay described in the Examples, below.

Unless otherwise indicated, the terms “halogen” and “halo” encompassfluorine, chlorine, bromine, and iodine.

Unless otherwise indicated, the term “heteroalkyl” refers to an alkylmoiety (e.g., linear, branched or cyclic) in which at least one of itscarbon atoms has been replaced with a heteroatom (e.g., N, O or S).

Unless otherwise indicated, the term “heteroaryl” means an aryl moietywherein at least one of its carbon atoms has been replaced with aheteroatom (e.g., N, O or S). Examples include acridinyl,benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl,benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl,indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl,pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, andtriazinyl.

Unless otherwise indicated, the term “heteroarylalkyl” or“heteroaryl-alkyl” means a heteroaryl moiety bound to an alkyl moiety.

Unless otherwise indicated, the term “heterocycle” refers to anaromatic, partially aromatic or non-aromatic monocyclic or polycyclicring or ring system comprised of carbon, hydrogen and at least oneheteroatom (e.g., N, O or S). A heterocycle may comprise multiple (i.e.,two or more) rings fused or bound together. Heterocycles includeheteroaryls. Examples include benzo[1,3]dioxolyl,2,3-dihydro-benzo[1,4]dioxinyl, cinnolinyl, furanyl, hydantoinyl,morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl,pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl and valerolactamyl.

Unless otherwise indicated, the term “heterocyclealkyl” or“heterocycle-alkyl” refers to a heterocycle moiety bound to an alkylmoiety.

Unless otherwise indicated, the term “heterocycloalkyl” refers to anon-aromatic heterocycle.

Unless otherwise indicated, the term “heterocycloalkylalkyl” or“heterocycloalkyl-alkyl” refers to a heterocycloalkyl moiety bound to analkyl moiety.

Unless otherwise indicated, the terms “managing cancer,” “managingcancer” and “management of cancer” mean reducing the rate of growth ofcancerous cells.

Unless otherwise indicated, the term “pharmaceutically acceptable salts”refers to salts prepared from pharmaceutically acceptable non-toxicacids or bases including inorganic acids and bases and organic acids andbases. Suitable pharmaceutically acceptable base addition salts include,but are not limited to, metallic salts made from aluminum, calcium,lithium, magnesium, potassium, sodium and zinc or organic salts madefrom lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocaine. Suitable non-toxic acids include, but are not limited to,inorganic and organic acids such as acetic, alginic, anthranilic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic,glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phenylacetic, phosphoric, propionic, salicylic, stearic, succinic,sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric,sulfuric, and methanesulfonic acids. Examples of specific salts thusinclude hydrochloride and mesylate salts. Others are well-known in theart. See, e.g., Remington's Pharmaceutical Sciences (18th ed., MackPublishing, Easton Pa.: 1990) and Remington: The Science and Practice ofPharmacy (19th ed., Mack Publishing, Easton Pa.: 1995).

Unless otherwise indicated, the term “potent deoxycytidine kinaseinhibitor” means a compound that has a dCK_IC₅₀ of less than about 1 μM.

Unless otherwise indicated, the terms “prevent cancer,” “preventingcancer” and “prevention of cancer” mean inhibiting the growth ofcancerous cells.

Unless otherwise indicated, a “prophylactically effective amount” of acompound is an amount sufficient to prevent a disease or condition, orone or more symptoms associated with the disease or condition, or toprevent its recurrence. A prophylactically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other agents, which provides a prophylactic benefit in theprevention of the disease or condition. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

Unless otherwise indicated, the term “stereomerically enrichedcomposition of” a compound refers to a mixture of the named compound andits stereoisomer(s) that contains more of the named compound than itsstereoisomer(s). For example, a stereoisomerically enriched compositionof (S)-butan-2-ol encompasses mixtures of (S)-butan-2-ol and(R)-butan-2-ol in ratios of, e.g., about 60/40, 70/30, 80/20, 90/10,95/5, and 98/2.

Unless otherwise indicated, the term “stereomerically pure” means acomposition that comprises one stereoisomer of a compound and issubstantially free of other stereoisomers of that compound. For example,a stereomerically pure composition of a compound having one stereocenterwill be substantially free of the opposite stereoisomer of the compound.A stereomerically pure composition of a compound having twostereocenters will be substantially free of other diastereomers of thecompound. A typical stereomerically pure compound comprises greater thanabout 80% by weight of one stereoisomer of the compound and less thanabout 20% by weight of other stereoisomers of the compound, greater thanabout 90% by weight of one stereoisomer of the compound and less thanabout 10% by weight of the other stereoisomers of the compound, greaterthan about 95% by weight of one stereoisomer of the compound and lessthan about 5% by weight of the other stereoisomers of the compound,greater than about 97% by weight of one stereoisomer of the compound andless than about 3% by weight of the other stereoisomers of the compound,or greater than about 99% by weight of one stereoisomer of the compoundand less than about 1% by weight of the other stereoisomers of thecompound.

Unless otherwise indicated, the term “substituted,” when used todescribe a chemical structure or moiety, refers to a derivative of thatstructure or moiety wherein one or more of its hydrogen atoms issubstituted with an atom, chemical moiety or functional group such as,but not limited to, alcohol, aldehylde, alkoxy, alkanoyloxy,alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl),alkynyl, alkylcarbonyloxy (—OC(O)alkyl), amide (—C(O)NH-alkyl- or-alkylNHC(O)alkyl), amidinyl (—C(NH)NH-alkyl or —C(NR)NH₂), amine(primary, secondary and tertiary such as alkylamino, arylamino,arylalkylamino), aroyl, aryl, aryloxy, azo, carbamoyl (—NHC(O)O-alkyl-or —OC(O)NH-alkyl), carbamyl (e.g., CONH₂, as well as CONH-alkyl,CONH-aryl, and CONH-arylalkyl), carbonyl, carboxyl, carboxylic acid,carboxylic acid anhydride, carboxylic acid chloride, cyano, ester,epoxide, ether (e.g., methoxy, ethoxy), guanidino, halo, haloalkyl(e.g., —CCl₃, —CF₃, —C(CF₃)₃), heteroalkyl, hemiacetal, imine (primaryand secondary), isocyanate, isothiocyanate, ketone, nitrile, nitro,oxygen (i.e., to provide an oxo group), phosphodiester, sulfide,sulfonamido (e.g., SO₂NH₂), sulfone, sulfonyl (including alkylsulfonyl,arylsulfonyl and arylalkylsulfonyl), sulfoxide, thiol (e.g., sulfhydryl,thioether) and urea (—NHCONH-alkyl-).

Unless otherwise indicated, a “therapeutically effective amount” of acompound is an amount sufficient to provide a therapeutic benefit in thetreatment or management of a disease or condition, or to delay orminimize one or more symptoms associated with the disease or condition.A therapeutically effective amount of a compound means an amount oftherapeutic agent, alone or in combination with other therapies, whichprovides a therapeutic benefit in the treatment or management of thedisease or condition. The term “therapeutically effective amount” canencompass an amount that improves overall therapy, reduces or avoidssymptoms or causes of a disease or condition, or enhances thetherapeutic efficacy of another therapeutic agent.

Unless otherwise indicated, the terms “treat cancer,” “treating cancer”and “treatment of cancer” mean causing apoptosis of cancerous cells.

Unless otherwise indicated, the term “include” has the same meaning as“include, but are not limited to,” and the term “includes” has the samemeaning as “includes, but is not limited to.” Similarly, the term “suchas” has the same meaning as the term “such as, but not limited to.”

Unless otherwise indicated, one or more adjectives immediately precedinga series of nouns is to be construed as applying to each of the nouns.For example, the phrase “optionally substituted alky, aryl, orheteroaryl” has the same meaning as “optionally substituted alky,optionally substituted aryl, or optionally substituted heteroaryl.”

It should be noted that a chemical moiety that forms part of a largercompound may be described herein using a name commonly accorded it whenit exists as a single molecule or a name commonly accorded its radical.For example, the terms “pyridine” and “pyridyl” are accorded the samemeaning when used to describe a moiety attached to other chemicalmoieties. Thus, the two phrases “XOH, wherein X is pyridyl” and “XOH,wherein X is pyridine” are accorded the same meaning, and encompass thecompounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol.

It should also be noted that any atom shown in a drawing withunsatisfied valences is assumed to be attached to enough hydrogen atomsto satisfy the valences. In addition, chemical bonds depicted with onesolid line parallel to one dashed line encompass both single and double(e.g., aromatic) bonds, if valences permit. Structures that representcompounds with one or more chiral centers, but which do not indicatestereochemistry (e.g., with bolded or dashed lines), encompasses purestereoisomers and mixtures (e.g., racemic mixtures) thereof. Similarly,names of compounds having one or more chiral centers that do not specifythe stereochemistry of those centers encompass pure stereoisomers andmixtures thereof.

5.2. Compounds of the Invention

This invention encompasses compounds of formula I:

and pharmaceutically acceptable salts and solvates thereof, wherein: L₁is a bond (i.e., the nitrogen is directly bound to A), —C(O)—, —SO₂—, or—C(R₄)₂—; A is optionally substituted alkyl, aryl or heterocycle; R₁ ishydrogen, halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OR₄, or optionallysubstituted alkyl; R₂ is hydrogen, halogen, —OH, —NH₂, —NO₂, —CN,—C(O)OR₄, or optionally substituted alkyl; each R₃ is independently ═Oor optionally substituted lower alkyl; each R₄ is independently hydrogenor lower alkyl; n is 1-3; and m is 0-3 if n is 1, m is 0-4 if n is 2, orm is 0-5 if n is 3.

Also encompassed are compounds of formula II:

and pharmaceutically acceptable salts and solvates thereof, wherein: L₁is a bond (i.e., the nitrogen is directly bound to A₁), —C(O)—, —SO₂—,or —C(R₄)₂—; A₁ is optionally substituted cycloalkyl, aryl orheterocycle; R₁ is hydrogen, halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OR₄, oroptionally substituted alkyl; R₂ is hydrogen, halogen, —OH, —NH₂, —NO₂,—CN, —C(O)OR₄, or optionally substituted alkyl; each R₃ is independently═O or optionally substituted lower alkyl; each R₄ is independentlyhydrogen or lower alkyl; n is 1-3; and m is 0-3 if n is 1, m is 0-4 if nis 2, or m is 0-5 if n is 3.

Some compounds of formula II are such that at least one of the followingis true: 1) n is not 1; 2) A₁ is not optionally substituted phenyl; 2)A₁ is not optionally substituted cycloalkyl; 3) A₂ is not optionallysubstituted heterocycle; 4) R₁ is not cyano or lower alkyl; 5) R₂ is notcyano or lower alkyl; 6) R₃ is not oxo; 7) m is 0; and/or 8) when n is1, L₁ is a bond, and A₁ is optionally substituted phenyl, R₃ is not oxo.

Also encompassed are compounds of formula III:

and pharmaceutically acceptable salts and solvates thereof, wherein: L₁is a bond (i.e., the nitrogen is directly bound to A₁), —C(O)—, —SO₂—,or —C(R₄)₂—; L₂ is a bond (i.e., A₁ is directly bound to A₂), —O—,—C(O)—, —SO₂—, —C(NOH)—, or —C(R₅)₂—; A₁ is optionally substitutedcycloalkyl, aryl or heterocycle; A₂ is optionally substitutedcycloalkyl, aryl or heterocycle; R₁ is hydrogen, halogen, —OH, —NH₂,—NO₂, —CN, —C(O)OR₄, or optionally substituted alkyl; R₂ is hydrogen,halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OR₄, or optionally substitutedalkyl; each R₃ is independently ═O or optionally substituted loweralkyl; each R₄ is independently hydrogen or lower alkyl; each R₅ isindependently hydrogen, fluoro, hydroxyl or lower alkyl, provided thatwhen one of R₅ is hydroxyl, the other is neither hydroxyl nor fluoro; nis 1-3; and m is 0-3 if n is 1, m is 0-4 if n is 2, or m is 0-5 if n is3.

Some compounds of formula III are such that at least one of thefollowing is true: 1) n is not 1; 2) A₁ is not optionally substitutedphenyl; 2) A₁ is not optionally substituted cycloalkyl; 3) A₂ is notoptionally substituted heterocycle; 4) R₁ is not cyano or lower alkyl;5) R₂ is not cyano or lower alkyl; 6) R₃ is not oxo; 7) m is 0; 8) whenn is 1, L₁ is a bond, and A₁ is optionally substituted phenyl, R₃ is notoxo; 9) L₂ is not —C(O)—; and/or 10) when n is 2, R₁ is methyl, R₂ ishydrogen, A₁ is pyridyl, and L₂ is —C(O)—, A₂ is not pyrrolidine.

Some compounds of the invention are of the formula:

wherein: each R₆ is halogen, —OH, —NH₂, —NO₂, —CN, or optionallysubstituted alkyl; and p is 0-2.

Some are of the formula:

Others are of the formula:

wherein: each R6 is halogen, —OH, —NH₂, —NO₂, —CN, or optionallysubstituted alkyl; and q is 0-4.

Some compounds are of the formula:

wherein: each R₇ is halogen, —OR₈, —NH₂, —NO₂, —C(O)N(R₈)₂, —CN, oroptionally substituted alkyl, aryl or heterocycle; each R₈ is hydrogenor optionally substituted alkyl; and r is 0-5.

In some compounds encompassed by the various formulae disclosed herein,as applicable (i.e., the formulae having the particular variablediscussed), L₁ is a bond. In others, L₁ is —C(O)— or —SO₂—. In others,L₁ is —C(R₄)₂— and, for example, at least one R₄ is hydrogen.

In some compounds, L₂ is a bond. In others, L₂ is —O—. In others, L₂ is—C(O)— or —C(NOH)—. In others, L₂ is —C(R₅)₂— and, for example, each R₅is hydrogen or one R₅ is not hydrogen.

In some compounds, L₁ is a bond and L₂ is —O—.

In some compounds, A₁ is optionally substituted aryl (e.g., monocyclicaryl). In some, A₁ is optionally substituted phenyl or naphthyl. Inothers, A₁ is optionally substituted heterocycle (e.g., monocyclicheterocycle). In some, the heterocycle is aromatic; in others, it isnot. In some, the heterocycle is optionally substituted imidazole,pyridine, pyrimidine, purine, triazine, or thiazole. In some, A₁ isoptionally substituted with one or more of: alkyl (e.g., lower alkyl),alkoxy (e.g., lower alkoxy), amino, cyano, halogen, or hydroxy.

In some compounds, A₂ is optionally substituted aryl (e.g., monocyclicaryl). In some, the aryl is optionally substituted phenyl or naphthyl.In others, A₂ is optionally substituted heterocycle (e.g., monocyclicheterocycle). In some, the heterocycle is aromatic; in others, it isnot. In some, the heterocycle is optionally substituted pyridine,quinoline, thiophene, indole, pyrazole, piperidine, morpholine, orpyrrolidine. In some, A₂ is optionally substituted with one or more of:alkyl (e.g., lower alkyl), alkoxy (e.g., lower alkoxy), amide, amino,cyano, halogen, hydroxy, sulfonamide or sulfone. In some, A₂ issubstituted with an optionally substituted heterocycle (e.g., anon-aromatic heterocycle).

In some compounds, R₁ is hydrogen or halogen. In others, R₁ is —OH, —NH₂or optionally substituted lower alkyl. In others, R₁ is —NO₂ or —CN.

In some compounds, R₂ is hydrogen or halogen. In others, R₂ is —OH, —NH₂or optionally substituted lower alkyl. In others, R₂ is —NO₂ or —CN.

In some compounds, R₁ is halogen and R₂ is hydrogen.

In some compounds, R₃ is hydrogen.

In some compounds, m is 0.

In some compounds, n is 1. In others, n is 2. In others, n is 3.

Compounds of the invention may contain one or more stereocenters, andcan exist as mixtures of enantiomers or diastereomers. This inventionencompasses stereomerically pure forms of such compounds, as well asmixtures of those forms. Stereoisomers may be asymmetrically synthesizedor resolved using standard techniques such as chiral columns or chiralresolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racematesand Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., etal., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of CarbonCompounds (McGraw Hill, N.Y., 1962); and Wilen, S. H., Tables ofResolving Agents and Optical Resolutions, p. 268 (E. L. Eliel, Ed.,Univ. of Notre Dame Press, Notre Dame, 1N, 1972).

Preferred compounds are potent deoxycytidine kinase inhibitors. Forexample, particular compounds have a dCK_IC₅₀ of less than about 1000,500, 250, 100, 50, 10, 5, 2.5 or 1 nM.

Particular compounds inhibit thymidine kinase with an IC₅₀ of greaterthan about 1, 2.5, 5 or 10 μM, as determined using the assay describedin the Examples below.

Particular compounds inhibit uridine kinase with an IC₅₀ of greater thanabout 1, 2.5, 5 or 10 μM, as determined using the assay described in theExamples below.

5.3. Methods of Treatment

This invention encompasses a method of reducing (e.g., inhibiting) theactivity of deoxycytidine kinase, which comprises contactingdeoxycytidine kinase with a compound of the invention (i.e., a compounddisclosed herein). In one embodiment, the deoxycytidine kinase is invitro. In another, the deoxycytidine kinase is in vivo.

Also encompassed is a method of treating, managing or preventing cancerin a patient, which comprises inhibiting deoxycytidine kinase activityin the patient. A particular patient is undergoing chemotherapy.

One embodiment of the invention encompasses a method of treating,managing or preventing cancer in a patient, which comprisesadministering to the patient a therapeutically or prophylacticallyeffective amount of a potent deoxycytidine kinase inhibitor. Particularpotent deoxycytidine kinase inhibitors are disclosed herein. In onemethod, the potent deoxycytidine kinase inhibitor is administeredadjunctively with another chemotherapeutic agent (e.g., cyclophosphamideor a combination comprising it, such as CHOP).

Cancers include solid cancers (e.g., colon carcinomas, brain tumors,head and neck tumors, malignant melanomas and soft tissue sarcomas),leukemia, and lymphoma.

Another embodiment of the invention encompasses a method of improvingthe effectiveness of a chemotherapeutic agent in a patient undergoingchemotherapy with the chemotherapeutic agent, which comprises inhibitingdeoxycytidine kinase activity in the patient. Examples ofchemotherapeutic agents include cyclophosphamide.

In each of these various methods, the amount, route of administrationand dosing schedule of a compound will depend upon factors such as thespecific indication to be treated, prevented, or managed, and the age,sex and condition of the patient. The roles played by such factors arewell known in the art, suitable doses and dosing regimens can bedetermined by the skilled artisan.

5.4. Pharmaceutical Compositions

This invention encompasses pharmaceutical compositions and dosage formscomprising compounds of the invention as their active ingredients.Pharmaceutical compositions and dosage forms of this invention mayoptionally contain one or more pharmaceutically acceptable carriers orexcipients. Certain pharmaceutical compositions are single unit dosageforms suitable for oral, topical, mucosal (e.g., nasal, pulmonary,sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous,intravenous, bolus injection, intramuscular, or intraarterial), ortransdermal administration to a patient. Examples of dosage formsinclude, but are not limited to: tablets; caplets; capsules, such assoft elastic gelatin capsules; cachets; troches; lozenges; dispersions;suppositories; ointments; cataplasms (poultices); pastes; powders;dressings; creams; plasters; solutions; patches; aerosols (e.g., nasalsprays or inhalers); gels; liquid dosage forms suitable for oral ormucosal administration to a patient, including suspensions (e.g.,aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or awater-in-oil liquid emulsions), solutions, and elixirs; liquid dosageforms suitable for parenteral administration to a patient; and sterilesolids (e.g., crystalline or amorphous solids) that can be reconstitutedto provide liquid dosage forms suitable for parenteral administration toa patient.

The formulation should suit the mode of administration. For example,oral administration may require enteric coatings to protect the activeingredient from degradation within the gastrointestinal tract. Inanother example, the active ingredient may be administered in aliposomal formulation to shield it from degradative enzymes, facilitatetransport in circulatory system, and/or effect delivery across cellmembranes to intracellular sites.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of a disease may contain larger amounts of one ormore of the active ingredients it comprises than a dosage form used inthe chronic treatment of the same disease. Similarly, a parenteraldosage form may contain smaller amounts of one or more of the activeingredients it comprises than an oral dosage form used to treat the samedisease. These and other ways in which specific dosage forms encompassedby this invention will vary from one another will be readily apparent tothose skilled in the art. See, e.g., Remington's PharmaceuticalSciences, 18th ed., Mack Publishing, Easton Pa. (1990).

6. EXAMPLES

The preparation of some compounds of the invention is described below.Methods used to determine biological activities of compounds are alsodescribed.

6.1. Chromatographic Conditions

Some of the following examples describe high performance liquidchromatography (HPLC) results. The HPLC conditions used to obtain thoseresults are summarized in Table 1:

TABLE 1 Solvent Mthd Column A B Time Grad Flow Obs A Sunfire C18 5 u 10mM CH₃CN 2 10-90 3.5 220 4.6 × 50 mm NH₄OAc B Sunfire C18 5 u 0.1% TFA0.1% TFA 2 10-90 3.5 220 4.6 × 50 mm in water in MeOH C Sunfire C18 5 u0.1% TFA 0.1% TFA 2 10-90 4 220 4.6 × 50 mm in water in MeOH D ShimPackVP- 10 mM CH₃CN 4  0-100 3 220 ODS 4.6 × 50 mm NH₄OAc E ShimPack VP-0.1% TFA 0.1% TFA 4 10-90 3 220 ODS 4.6 × 50 mm in water in MeOH FSunfire C18 5 u water 0.1% TFA 6 30-80 3.5 220 4.6 × 50 mm in MeOH GSunfire C18 5 u water 0.1% TFA 3 10-90 3.5 220 4.6 × 50 mm in MeOH HSunfire C18 5 u water 0.1% TFA 2 10-90 3.5 220 4.6 × 50 mm in MeOH ISunfire C18 5 u water 0.1% TFA 3 10-75 3.5 220 4.6 × 50 mm in MeOH JLuna 10 mM CH₃CN 8 10-90 2 220 Phenylhexyl 5 u NH₄OAc 4.6 × 50 mm KSunfire C18 5 u 90:10 H₂O/ 10:90 H₂O/ 2  0-100 3.5 220 4.6 × 50 mm MeOHMeOH with 0.1% with 0.1% TFA TFA L ShimPack VP- 10 mM CH₃CN 4 10-90 3220 ODS 4.6 × 50 mm NH₄OAc M Sunfire C18 5 u 10 mM CH₃CN 2 10-90 3 2204.6 × 50 mm NH₄OAc N Luna 10 mM CH₃CN 3 10-90 3 220 Phenylhexyl 5 uNH₄OAc 4.6 × 50 mm O Sunfire C18 5 u 10 mM CH₃CN 3  0-100 3.5 220 4.6 ×50 mm NH₄OAc P Sunfire C18 3.5 u 10 mM CH₃CN 2.8 10-95 4.5 220 4.6 × 50mm NH₄OAc Q ShimPack VP- 10 mM CH₃CN 8 10-90 3 220 ODS 4.6 × 50 mmNH₄OAc R Sunfire C18 5 u 10 mM CH₃CN 4 10-90 3.5 220 4.6 × 50 mm NH₄OAcS Luna 10 mM CH₃CN 3  5-100 3 220 Phenylhexyl 5 u NH₄OAc 4.6 × 50 mm TLuna 10 mM CH₃CN 8  5-100 3 220 Phenylhexyl 5 u NH₄OAc 4.6 × 50 mm USunfire C18 5 u 10 mM CH₃CN 3  5-100 3.5 220 4.6 × 50 mm NH₄OAc VSunfire C18 5 u 10 mM CH₃CN 2  5-100 3.5 220 4.6 × 50 mm NH₄OAc WSunfire C18 5 u 10 mM CH₃CN 3 20-90 3.5 220 4.6 × 50 mm NH₄OAc X SunfireC18 5 u 10 mM CH₃CN 3  5-100 3.5 220 4.6 × 50 mm NH₄OAc Y Sunfire C18 5u 10 mM CH₃CN 3 10-90 3.5 220 4.6 × 50 mm NH₄OAc Z Sunfire C18 5 u 10 mMCH₃CN 3  5-90 3.5 220 4.6 × 50 mm NH₄OAc AA Sunfire C18 5 u 90:10 H₂O/10:90 H₂O/ 3  5-100 3.5 220 4.6 × 50 mm MeOH MeOH with 0.1% with 0.1%TFA TFAwherein: Mthd is the method; Flow is the flow rate in ml/min; Time isthe gradient duration in minutes; Grad is the solvent gradient (percentB); and Obs is the observation wavelength in nm.

6.2. General Method A Preparation of5-fluoro-2-(piperidin-4-yloxy)pyrimidin-4-amine (4)

A general synthetic approach referred to herein as General Method A wasused to prepare the captioned compound.

In this exemplification, a 500 mL round bottom flask fitted with stirbarwas charged with 1 (13.00 g 100 mmol), 2 (10.0 g, 49.7 mmol),triphenylphosphine (19.6 g, 74.6 mmol) and anhydrous THF (1 L). To thismixture was added, via syringe, diethyl diazene-1,2-dicarboxylate (DEAD;13.0 g, 74.6 mmol). The reaction mixture was stirred at ambienttemperature for 18 h under N₂ atmosphere. Precipitate was filtered offand filtrate preabsorbed onto silica gel and passed through a plug ofsilica gel, eluting with EtOAc Hexanes 1:4. Recovered 25 g crude 3 whichwas taken on for deprotection.

To a 1 L round bottom flask charged with 25 g of 3 was added 200 ml EtOHand 50 mL conc. HCl. The reaction was stirred at ambient temperature for18 h. Evaporated in vacuo and the residue partitioned between 1:1EtOAc:Et₂O and water. Organics were extracted 3 times with water andcombined aqueous layers were evaporated in vacuo and dried to afford awhite solid (8.3 g, 59% yield).

Using this procedure 3-pyrrolidinol and azepan-4-ol react with 2 to formcommon intermediate 5-fluoro-2-(pyrrolidin-3-yloxy)pyrimidin-4-amine and5-Fluoro-2-(-(azepan-4-yloxy)pyrimidin-4-amine respectively.

6.3. General Method B Preparation of5-fluoro-2-(piperidin-4-yloxy)pyrimidin-4-amine (4)

A general synthetic approach referred to herein as General Method B wasused to prepare the captioned compound.

In this exemplification, to a 250 mL 3-neck round bottom flask wascharged 5 (7.38 g, 50 mmol), 2 (20.13 g, 2.0 equiv), NaO-t-Bu (9.61 g,2.0 equiv) and diglyme (100 mL) and the mixture was heated at 120° C.for 18 h. The mixture was then cooled to 50° C. and H₂O (100 mL) wasadded. The mixture was extracted with EtOAc (200 mL) and washed with amixture of H₂O (50 mL) and brine (50 mL) twice. The organic layer wasdried over MgSO₄ and concentrated under vacuum. The residue was thenpurified by silica gel column chromatography using hexanes:EtOAc (2:1)to give the title compound 6 as a white solid (9.05 g, 58% yield).

Removal of the Boc group was accomplished as described in General MethodA.

Scheme 2 can also be employed when the 4-Hydroxy-piperidine has alreadybeen N-capped.

6.4. General Method C Preparations of5-fluoro-2-(1-(5-fluoro-6-(4-methoxyphenoxy)-pyrimidin-4-yl)piperidin-4-yloxy)pyrimidin-4-amine(10) and2-(6-(4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidin-1-yl)pyrimidin-4-yloxy)benzonitrile(14) (Schemes 3 & 4)

A general synthetic approach referred to herein as General Method C wasused to prepare the captioned compound.

In this exemplification, to a 50 mL round bottom flask fitted with astirbar and charged with 7 (280 mg, 2.1 mmol) in n-BuOH cooled to 0° C.was added N,N-diisopropylethylamine (DIEA) (1 mL, 6.3 mmol) and 4. Thereaction was stirred at 0° C. for 1 hr. The reaction mixture was allowedto warm to room temperature and evaporated in vacuo and purified on aplug of SiO₂. A white solid 8 was recovered (640 mg, 83% yield) whichwas taken on without further purification.

Crude 8 (100 mg, 0.31 mmol) was added to a microwave vial along with 2mL of anhydrous DMF, 9 (76 mg, 0.31 mmol) and NaH (25 mg, 062 mmol). Themixture was heated in the microwave for 10 min at 160° C. (75 W). Thecrude reaction mixture was evaporated in vacuo and the residue treatedwith MeOH and water. The solids were filtered off, washed with water anddried to afford product 10 (47 mg, 35% yield).

This procedure is a two-step, one pot process. A microwave vial wascharged with 11 (500 mg, 3.36 mmol), 12 (400 mg, 3.36 mmol) and K₂CO₃(464 mg, 3.36 mmol) in DMF (5 mL) and was heated to 100° C. for 5minutes in the microwave. The aryl ether 13 was generated as a stableintermediate and was carried on without further isolation andpurification. An aliquot (3 mL, 2.01 mmol) of the reaction mixture wassyringed over to a new microwave vial to which was added DIEA (1 mL,5.74 mmol) and 4 (630 mg, 2.22 mmol) and the reaction was heated to 200°C. for 10 minutes under microwave irradiation. The reaction mixture wasevaporated in vacuo and the residue was dissolved in MeOH and water wasadded until the solution became cloudy. After sitting over night, thesolid was filtered off, dissolved in hot MeOH and warm water was addeduntil cloudy. Let sit overnight and filtered off white solid 14 (154 mg,19% yield).

In a similar fashion other nucleophiles (alcohols, anilines, etc) andbases can be used.

Intermediates similar to 8, 10, 13 and 14 were synthesized as outlinedabove and served as starting materials for other methods.

6.5. General Method D Preparation of4-amino-1-(1-(2,3-dichlorophenylsulfonyl)piperidin-4-yl)-5-fluoroppyridin-2(1H)-one(16)

A general synthetic approach referred to herein as General Method D wasused to prepare the captioned compound.

In this exemplification, compound 4 (60 mg, 0.21 mmol) and DIEA (0.1 mL,0.63 mmol) were mixed in DCM (2 mL). Compound 15 (62 mg, 0.25 mmol, 1.2eq) was then added. The mixture was stirred at room temperature for 1hour. The product was isolated by evaporation in vacuo followed bypurification using reverse phase HPLC (aqueous ammoniumacetate/acetonitrile). Isolated product 16 as a white solid (32 mg, 36%yield).

6.6. General Method E Preparation of(4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidin-1-yl)(2-(4-methoxyphenoxy)phenyl)methanone(18)

A general synthetic approach referred to herein as General Method E wasused to prepare the captioned compound.

In this exemplification, compound 17 (100 mg, 0.25 mmol), 9 (47.12 mg,0.38 mmol), Tetrakis(acetonitrile)copper(I) hexafluorophosphate (4.7 mg,0.013 mmol), and Cs₂CO₃ (163 mg, 0.50 mmol) were mixed in 1,4-dioxane (1mL). The reaction mixture was heated under microwave irradiation at 180°C. for 10 minutes. The reaction mixture was purified by preparative HPLC(aqueous ammonium acetate/acetonitrile). Isolated 18 as a white solid(1.5 mg, 1% yield).

6.7. General Method F Preparation of2-(1-(6-chloro-5-fluoropyrimidin-4-yl)piperidin-4-yloxy)-5-fluoropyrimidin-4-amine(20)

A general synthetic approach referred to herein as General Method F wasused to prepare the captioned compound.

In this exemplification, to a 20 mL microwave vial charged with astirring bar and 8 (1.00 g, 3.07 mmol) was added 1N NaOH (8 mL). Thecapped vial was heated to 120° C. in a microwave reactor for 20 minutesduring which time the reaction solution became homogeneous. Aftercooling to room temperature, the pH of the reaction mixture was adjustedto 4-5 with 1N HCl aqueous solution and a white solid precipitated out.The solid 19 was filtered off and dried (1.02 g, quantitative yield).

In a 50 mL round bottom flask charged with a magnetic stirring bar, 19(0.324 g, 1 mmol) was mixed with POCl₃ (2 mL). The mixture was heated to110° C. and refluxed for 2 hours. After cooling down, POCl₃ was removedin vacuo, and the residue was dissolved in EtOAc (50 mL) and 5% NaHCO₃(20 mL). After shaking and separation, the organic phase was dried overNa₂SO₄. Removal of the solvent gave a yellow solid as product 20 (0.284g, 83% yield).

6.8. General Method G(6-(4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidin-1-yl)pyrimidin-4-yl)(5-chloroindolin-1-yl)methanone(25)

A general synthetic approach referred to herein as General Method G wasused to prepare the captioned compound.

In this exemplification, to a pre-dried Schlenk flask charged with amagnetic stirring bar and 21 (1.0 g, 3.09 mmol) and K₂CO₃ (0.64 g, 4.63mmol) was added a solution of iso-propanol (30 mL, anhydrous) and DMF (6mL, anhydrous). After degassing for 10 minutes by flowing N₂ through thesolution, Pd(OAc)₂ (0.070 g, 0.31 mmol) and DPPP (0.140 g, 0.34 mmol)were added. After vacuum evacuation of the flask and flushing with CO (3times), CO (1 atm) was applied to reaction. Reaction mixture was heatedto 80° C. and for 18 h. After cooling to room temperature, the solventwas removed in vacuo. The residue was transferred to a separatory funnelusing DCM and water. After extraction and separation, the aqueous layerwas washed with 50 mL of DCM. The organic layers were combined andsolvent removed. The residue was purified by silica gel column (4:96MeOH:DCM). Removal of the solvent in vacuo gave a white solid product22. (0.992 g, 85% yield).

In a 100 mL round bottom flask charged with a stirring bar, 22 (0.99 g,2.63 mmol) was stirred in THF (10 mL) and water (10 mL). 3M NaOH (3 mL,9 mmol) was added. The reaction mixture was heated to 50° C. and stirredfor 2 hours. After cooling to room temperature the reaction mixture wasadjusted to pH 5. Most of solvent was removed in vacuo and a precipitateformed. The precipitate was filtered off and washed twice with a smallamount of water. Drying of the white solid under high vacuum gave 23(0.796 g, 91% yield).

In a 40 mL vial with a magnetic stirring bar, 23 (0.083 g, 0.246 mmol)was mixed with 24 (74 mg, 0.492 mmol) and triethylamine (0.050 g, 0.492mmol) in DMF (10 mL). 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU) (0.140 g, 0.369 mmol)was then added and the reaction was stirred at room temperature for 2hours. Then solvent was removed in vacuo. The residue was dissolved inDCM and washed with water. The organic phase was concentrated in vacuoand the residue was purified by silica gel chromatography (0 to 10% MeOHin DCM) to give a white solid 25 (64 mg, 56% yield).

6.9. General Method H Preparation of(4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidin-1-yl)(biphenyl-4-yl)methanone(27)

A general synthetic approach referred to herein as General Method H wasused to prepare the captioned compound.

In this exemplification, to a suspension of 26 (198 mg, 1.0 mmol) inanhydrous DCM (10 mL) was added oxalyl chloride (185 uL, 2.12 mmol) andthe reaction was stirred at room temperature until complete conversionto acid chloride was observed. The reaction was evaporated in vacuo andazeotroped with toluene. The residue was dissolved in acetonitrile andadded slowly to a suspension of 4 (225.0 mg, 1.06 mmol) in acetonitrile(10 mL) and sat. NaHCO₃ (5 mL), then stirred vigorously for 18 h.Evaporated in vacuo and partitioned between DCM and 0.5 N NaOH. Theorganic layer was washed with water and brine, dried with Na₂SO₄ andevaporated in vacuo. Purified by preparative HPLC (aqueous ammoniumacetate/acetonitrile). Recovered a white solid 27 (21 mg, 5.5% yield).

6.10. General Method I Preparation of1-(4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidin-1-yl)-2-(naphthalen-2-ylamino)ethanone(29)

A general synthetic approach referred to herein as General Method I wasused to prepare the captioned compound.

In this exemplification, compound of 28 was synthesized using GeneralMethod H. Compound 29 was synthesized using an appropriate amine andGeneral Method D.

6.11. General Method J Preparation of5-fluoro-2-(1-(3-(4-methoxyphenoxy)propyl)piperidin-4-yloxy)pyrimidin-4-amine(30)

A general synthetic approach referred to herein as General Method J wasused to prepare the captioned compound.

In this exemplification, compound 30 was synthesized using GeneralMethod C and the appropriate alkyl halide.

6.12. General Method K Preparation of(6-(4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidin-1-yl)pyrimidin-4-yl)(4-methoxyphenyl)methanone(34)

A general synthetic approach referred to herein as General Method K wasused to prepare the captioned compound.

In this exemplification, compound 31 (338 mg, 2.27 mmol), 32 (273 uL,2.25 mmol), 1-butyl-3-methylimidazolium tetrafluoroborate (150 mg, 0.66mmol) and THF (20 ml) were mixed well at RT in a round bottom flask, NaH(60% in mineral oil, 117 mg, 2.92 mmol) was then added. The resultingsolution was stirred at RT for 0.5 hour. The reaction was loaded ontoSiO₂ and purified by column chromatography (0 to 1% MeOH in DCM).Recovered 33 as a solid (40 mg, 7% yield).

Compound 33 (40 mg 0.16 mmol), 4 (60 mg, 0.21 mmol), excess DIEA and DMF(2 mL) were combined and mixed well in a 2 mL microwave vial and heatedin the microwave at 180° C. for 10 minutes. Product was isolated byevaporation in vacuo followed by purification on preparative HPLC(aqueous ammonium acetate/acetonitrile). Isolated 34 as a white solid(29 mg, 42% yield).

6.13. General Method L Preparation of2-(1-(6-(difluoro(4-methoxyphenyl)methyl)pyrimidin-4-yl)piperidin-4-yloxy)-5-fluoropyrimidin-4-amine(35)

A general synthetic approach referred to herein as General Method L wasused to prepare the captioned compound.

In this exemplification, compound 34 (20 mg, 0.094 mmol) was dissolvedin DCM (2 mL), (Diethylamino)sulfur trifluoride (148 uL 0.113 mmol) wasadded. The reaction mixture was refluxed for 3 hrs and then filteredthrough silica gel, washing with 8% MeOH/DCM. Concentrated byevaporation in vacuo and purified by reverse phase HPLC (aqueousammonium acetate/acetonitrile) to give 35 as a white solid (4.76 mg, 10%yield).

6.14. General Method M Preparation of(6-(4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidin-1-yl)pyrimidin-4-yl)(4-methoxyphenyl)methanol(36)

A general synthetic approach referred to herein as General Method M wasused to prepare the captioned compound.

In this exemplification, compound 34 (16 mg, 0.038 mmol) was dissolvedin 1 mL MeOH, NaBH₄ (1.7 mg, 0.045 mmol) was added and the reaction wasstirred at room temperature for 0.5 hour. The reaction mixture wastreated with a small amount of H₂O, then purified by reverse phase HPLC(aqueous ammonium acetate/acetonitrile). Recovered 36 as a white solid(6.8 mg. 42% yield).

6.15. General Method N Preparation of(E)-(6-(4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidin-1-yl)pyrimidin-4-yl)(4-methoxyphenyl)methanoneoxime (37)

A general synthetic approach referred to herein as General Method N wasused to prepare the captioned compound.

In this exemplification, compound 34 (115 mg 0.27 mmol), hydroxylaminehydrochloride (37 mg, 0.54 mmol), NaOAc (2.0 uL, 21 wt % in EtOH, 0.54mmol, 2 eq) were combined in 1:1 EtOH/THF (4 ml) and stirred at 50° C.for 0.5 hour. The reaction mixture was concentrated in vacuo andpurified on SiO₂ (4 to 5% MeOH in DCM). Treatment with MeOH (6 ml)precipitated the product, which was filtered and washed with MeOH.Isolated a white solid 37 (19 mg, 16% yield).

6.16. General Method O Preparation of2-(2-(6-(4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidin-1-yl)pyrimidin-4-yloxy)phenyl)propan-2-ol(39)

A general synthetic approach referred to herein as General Method O wasused to prepare the captioned compound.

In this exemplification, to a cooled (ice bath) solution of ketone 38(848 mg, 2 mmol) in THF (20 mL) was added methyl magnesium bromidesolution in ether (2.5 mL, 3 M, 7.5 mmol). The reaction was warmed to RTslowly over 1 h then stirred at RT for 3 hours before quenching withsaturated ammonium chloride. The product was extracted into ethylacetate, dried over sodium sulfate and concentrated to a yellow foam.The crude foam was purified by reverse phase HPLC (aqueous ammoniumacetate/acetonitrile) to give a white solid 39 (36 mg, 4% yield).

6.17. General Method P Preparation of5-fluoro-2-(1-(6-(2-(1-methyl-1H-pyrazol-4-yl)phenoxy)pyrimidin-4-yl)piperidin-4-yloxy)pyrimidin-4-amine(41)

A general synthetic approach referred to herein as General Method P wasused to prepare the captioned compound.

In this exemplification, to a solution of 40 (42 mg, 0.09 mmol) inethanol (4 mL) was added 1-methyl-pyrazoleboronic ester (37 mg, 0.18mmol) followed by 2 N sodium carbonate (0.4 mL, 0.4 mmol) andPd(dppf)Cl₂.CH₂Cl₂ (8 mg, 0.01 mmol). The reaction was sealed and heatedunder microwave irradiation at 100° C. for 10 min. The reaction wasfiltered and purified by reverse phase HPLC (aqueous ammoniumacetate/acetonitrile) to yield a white solid 41 (20 mg, 48% yield).

6.18. General Method Q Preparation of5-Fluoro-2-[1-(5-oxa-2,4-diaza-dibenz[a,d]-cyclohepten-1-yl)-piperidin-4-yloxy]-pyrimidin-4-ylamine(43)

A general synthetic approach referred to herein as General Method Q wasused to prepare the captioned compound.

In this exemplification, a solution of 42 (0.064 g, 0.147 mmol) intrifluorotoluene (3 mL) and 1,2-dichloroethane (3 mL) was treated with(1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium(0.001 g, 0.001 mmol). The mixture was heated under microwaveirradiation at 160° C. for 20 minutes. The mixture was concentrated invacuo, loaded on silica gel, and chromatographed (10 g SiO₂, 4:6hexane/ethyl acetate to ethyl acetate), followed by reverse phase HPLC(aqueous ammonium acetate/acetonitrile) to afford 43 as a white solid(0.002 g, 3% yield).

6.19. General Method R Preparation of2-(1-(5-amino-6-(4-methoxyphenoxy)pyrimidin-4-yl)piperidin-4-yloxy)-5-fluoropyrimidin-4-amine(45)

A general synthetic approach referred to herein as General Method R wasused to prepare the captioned compound.

In this exemplification, compound 44 (180 mg, 0.37 mmol) was sealed in aParr vessel with 10% Pd—C (20 mg) and ethanol (5 mL) and stirred under ahydrogen atmosphere of 10 psi for 30 minutes. The reaction mixture wasfiltered and purified by reverse phase HPLC(CH₃CN, 0.1% formic acid inH₂O) to give 45 (4 mg, 2.5% yield).

6.20. General Method S Preparation of2-(1-(2-benzyl-2H-tetrazol-5-yl)piperidin-4-yloxy)-5-fluoropyrimidin-4-amine(48)

A general synthetic approach referred to herein as General Method S wasused to prepare the captioned compound.

In this exemplification, compound 4 (500 mg, 1.8 mmol) and potassiumcarbonate (975 mg, 7.1 mmol) were stirred in DMF (10 mL) while cyanogenbromide (187 mg, 1.8 mmol) in DMF (1.5 mL) was added. After 1 hour,water (100 mL) was added and a pale yellow solid formed. The solid wascollected by filtration to afford the cyanamide 46 (237 mg, 56% yield).

Compound 46 (225 mg, 0.95 mmol) was suspended in 1:1 water/iso-propanol(6 mL). Sodium azide (124 mg, 1.9 mmol) and zinc bromide (427 mg, 1.9mmol) were added. The mixture was heated to reflux, capped, vented, andthen heated at 140° C. under microwave irradiation for 30 min. Thereaction was acidified with 1 M HCl and purified on reverse phase HPLC(0.1% TFA in water; 0.1% TFA in MeOH) to afford the desired tetrazole 47(253 mg, 96% yield).

The tetrazole 47 (50 mg, 0.18 mmol) obtained above was dissolved inethanol (8 mL), water (3 mL) and 1M NaOH (196 uL, 0.196 mmol).2-(bromomethyl)-benzonitrile (35 mg, 0.18 mmol) was added and thereaction heated to reflux. After 18 hours another portion of 1M NaOH(196 uL, 0.196 mmol) and 2-(bromomethyl)-benzonitrile (35 mg, 0.18 mmol)was added. After another 24 hours, the product was purified by reversephase HPLC (0.1% formic acid in water; 0.1% formic acid in MeOH) toafford the desired product 48 (10 mg, 14% yield).

6.21. General Method T Preparation of2-(1-(6-(4-(2-(dimethylamino)ethoxy)_(p)henoxy)pyrimidin-4-yl)piperidin-4-yloxy)-5-fluoropyrimidin-4-amine (50)

A general synthetic approach referred to herein as General Method T wasused to prepare the captioned compound.

In this exemplification, in a pre-dried 25 mL round bottom flask chargedwith a magnetic stirring bar, amide 49 (0.050 g, 0.1 mol) was dissolvedin 3 mL of THF. Lithium aluminum hydride (1M solution in THF, 0.2 mL,0.2 mmol) was added to the reaction which was stirred at roomtemperature for half an hour. Upon completion, the reaction was quenchedby consecutive additions of water (7 μL), 3 N NaOH (7 μL) and water (21μL). The reaction mixture was allowed to stir for 10 minutes. Theprecipitate was filtered the filtrate was concentrated. The cruderesidue purified by preparative HPLC (acetonitrile/aqueous ammoniumacetate) to give product 50 (10 mg, 22% yield).

6.22. General Method U Preparation of5-fluoro-2-(1-(6-phenylpyrimidin-4-yl)piperidin-4-yloxy)pyrimidin-4-amine(51)

A general synthetic approach referred to herein as General Method U wasused to prepare the captioned compound.

In this exemplification, compound 51 was synthesized using GeneralMethod P.

6.23. General Method V Preparation of(4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidin-1-yl)(5-(benzo[b]thiophen-2-yl)-2-fluorophenyl)methanone(53)

A general synthetic approach referred to herein as General Method V wasused to prepare the captioned compound.

In this exemplification, compound 53 was synthesized using GeneralMethods H and P.

6.24. General Method W Preparation ofN-(6-(4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidin-1-yl)pyrimidin-4-yl)benzamide(56)

A general synthetic approach referred to herein as General Method W wasused to prepare the captioned compound.

In this exemplification, compound 56 was synthesized using GeneralMethod H followed by General Method C.

6.25. General Method X Preparation of2-(1-(6-(4-((cyclopropylamino)methyl)-2-methoxyphenoxy)-5-fluoropyrimidin-4-yl)piperidin-4-yloxy)-5-fluoropyrimidin-4-amine(58)

A general synthetic approach referred to herein as General Method X wasused to prepare the captioned compound.

In this exemplification, aldehyde 57 (50 mg, 0.11 mmol), sodiumtriacetoxyborohydride (116 mg, 0.55 mmol) and cyclopropylamine (32 mg,0.55 mmol) were stirred in acetonitrile (3 mL) for 18 hours at roomtemperature. The reaction mixture was filtered and purified by reversephase HPLC(CH₃CN, 0.1% Formic Acid in H₂O) to give product 58 (25 mg,46% yield)

6.26. General Method Y Preparation of3-(6-(4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidin-1-yl)-5-fluoropyrimidin-4-yloxy)-5-methoxybenzonitrile(60)

A general synthetic approach referred to herein as General Method Y wasused to prepare the captioned compound.

In this exemplification, the phenol 59 (25 mg, 0.06 mmol) was stirred inacetone (3 mL) with potassium carbonate (39 mg, 0.28 mmol). A few dropsof methyl iodide (excess) were added to the reaction mixture which wasleft to stir for 1 hour at room temperature. The mixture wasconcentrated and purified by HPLC(CH₃CN, 0.1% formic acid in H₂O) togive the final product 60 (14 mg, 51% yield).

6.27. General Method Z Preparation of2-(1-(6-(difluoro(2-fluoro-4-methoxyphenyl)methyl)pyrimidin-4-yl)piperidin-4-yloxy)-5-fluoropyrimidin-4-amine(63)

A general synthetic approach referred to herein as General Method Z wasused to prepare the captioned compound.

In this exemplification, compound 61 (100 mg 0.38 mmol) was dissolved inDCM and (diethylamino)sulfur trifluoride (148 uL, 0.113 mmol) was added.The reaction mixture was refluxed for 8 hrs. Additional(diethylamino)sulfur trifluoride (148 uL, 0.113 mmol) was added andreflux resumed for 18 hours. Removed solvent in vacuo and crude product62 (200 mg) was used without further purification in the following step.

Half of the above crude reaction mixture was mixed with 4 (40 mg, 0.14mmol), DIEA (80 uL) in DMF (1 mL) and heated under microwave irradiationat 180° C. for 10 minutes. This reaction was repeated using theremaining amount of the crude 62. The two reaction mixtures werecombined and diluted with EtOAc, washed with H₂O three times. Organicsolvent was removed in vacuo, the residue was purified by preparativeHPLC with neutral mobile phase (aqueous ammonium acetate/acetonitrile).Isolated 63 as a light brown solid (40 mg, 31% yield).

6.28. General Method AA Preparation of3-(6-(4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidin-1-yl)-5-fluoropyrimidine-4-carbonyl)benzonitrile(65)

A general synthetic approach referred to herein as General Method AA wasused to prepare the captioned compound.

In this exemplification, compound 8200 mg 0.61 mmol), 64 (80 mg, 0.61mmol), 1-butyl-3-methylimidazolium tetrafluoroborate (27 uL, 0.12 mmol)and THF (3 mL) were mixed in a microwave reaction vial, NaH (60% inmineral oil; 24 mg 0.61 mmol) was then added. The reaction mixture washeated in the microwave at 170° C. for 10 minutes. The desired productwas purified by reverse phase HPLC (aqueous ammoniumacetate/acetonitrile). Recovered 65 as a white solid (41 mg, 15% yield).

6.29. General Method BB Preparation of2-(1-(6-(3,5-difluorobenzyl)pyrimidin-4-yl)piperidin-4-yloxy)-5-fluoropyrimidin-4-amine(67)

A general synthetic approach referred to herein as General Method BB wasused to prepare the captioned compound.

In this exemplification, compound 21 (contained about 20% DIEA.HCl salt,60 mg, about 0.15 mmol), (3,5-difluorobenzyl)zinc(II) bromide in THF (2ml, 0.5 M, 1 mmol), and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withCH₂Cl₂ (20 mg) were mixed well and heated at 120° C. for 20 minutes.Purified by SiO₂ (2-5% MeOH in DCM). Recovered 67 as a white solid (15mg, 24% yield).

6.30. General Method CC Preparation of4-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)-piperidin-1-yl]-6-(4-methoxy-phenoxy)-pyrimidine-5-carbonitrile(69)

A general synthetic approach referred to herein as General Method CC wasused to prepare the captioned compound.

In this exemplification, to a microwave vial charged with 68 (100 mg,0.20 mmol) and zinc cyanide (24 mg, 0.20 mmol) was added Pd(PPh₃)₄ (7mg, 0.006 mmol) in DMF (1 mL). The vial was flushed with nitrogen,sealed and heated at 220° C. for 20 min, after which time additionalzinc cyanide (50 mg, 0.42 mmol) and Pd(PPh₃)₄ (15 mg, 0.013 mmol) wereadded. The vial was again flushed with nitrogen, sealed and heated at220° C. for 20 min. The resulting suspension was filtered, concentratedto dryness and redissolved in CH₂Cl₂ and MeOH. The solution was passedthrough a plug of silica, concentrated to dryness and purified byreverse phase HPLC (aqueous ammonium acetate/acetonitrile) to afford 69(13 mg, 0.030 mmol, 15% yield).

6.31. Additional Compounds

Additional compounds of the invention are listed below in Table 2, alongwith information concerning the general methods (Mthd) used for theirpreparation, the measured masses of the compounds (M+1), HPLCinformation [method (retention time in minutes)], and, in some cases, areference to NMR information provided in Table 3.

TABLE 2 Compound Mthd M + 1 HPLC NMR 4-Amino-2-{1-[6-(5-cyano-2-methoxy-B 461.5 Y (2.27)  1 phenoxy)-5-fluoro-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidine-5-carbonitrile2-{1-[6-(3,5-Difluoro-benzyl)-pyrimidin-4-yl]- BB 417.1 A (1.70) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-[1-(6-Benzyl-pyrimidin-4-yl)-piperidin-4- BB 381.2 A (1.59)  2yloxy]-5-fluoro-pyrimidin-4-ylamine2-{1-[6-(2-Ethyl-phenoxy)-pyrimidin-4-yl]- C 411.1 B (1.91) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(3-Ethyl-biphenyl-4-yloxy)-pyrimidin-4- C 487.1 B (2.09) —yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(2-Ethyl-4-fluoro-phenoxy)-pyrimidin- C 429.1 B (1.86) —4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(4-methoxy-phenoxy)- C 413.0 B (1.52) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-{1-[6-(3-Ethyl-phenoxy)-pyrimidin-4-yl]- C 411.2 B (1.80) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(3-Chloro-phenoxy)-pyrimidin-4-yl]- C 417.0 B (3.07)  3piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(4-Ethyl-phenoxy)-pyrimidin-4-yl]- C 411.1 B (3.07) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(2-Ethyl-cyclohexyloxy)-pyrimidin-4- C 417.0 D —yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- (3.00/3.13) ylamine5-Fluoro-2-[1-(6-p-tolyloxy-pyrimidin-4-yl)- C 397.0 B (1.65) —piperidin-4-yloxy]-pyrimidin-4-ylamine2-{1-[6-(2-Chloro-phenoxy)-pyrimidin-4-yl]- C 417.0 M (1.72) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(4-Chloro-phenoxy)-pyrimidin-4-yl]- C 417.0 M (1.79) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(3-methoxy-phenoxy)- C 413.0 M (1.61) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-{1-[6-(2-Ethoxy-phenoxy)-pyrimidin-4-yl]- C 427.0 B (1.89) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(4-Chloro-2-methyl-phenoxy)- C 431.2 M (1.61) —pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(4-trifluoromethoxy-phenoxy)- C 467.2 B (1.98) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-[1-(6-o-tolyloxy-pyrimidin-4-yl)- C 397.2 B (1.57) —piperidin-4-yloxy]-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2-fluoro-phenoxy)-pyrimidin- C 401.1 R (2.61) —4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 408.0 S (2.18) —piperidin-1-yl]-pyrimidin-4-yloxy}-benzonitrile2-{1-[6-(2-Chloro-4-fluoro-phenoxy)-pyrimidin- C 435.0 M (1.79) —4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(2-methoxy-phenoxy)- C 413.2 A (1.46)  4pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(2-isopropoxy-phenoxy)- C 441.2 B (1.68) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-[1-(6-phenoxy-pyrimidin-4-yl)- C 383.2 C (2.67) —piperidin-4-yloxy]-pyrimidin-4-ylamine2-{1-[6-(2,4-Difluoro-phenoxy)-pyrimidin-4-yl]- C 419.2 M (1.62) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(2,4,6-trifluoro-phenoxy)- C 436.8 M (1.71) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-{1-[4-(2-Chloro-4-fluoro-phenoxy)-pyrimidin- C 434.8 M (1.88) —2-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 422.2 M (1.60) —piperidin-1-yl]-2-methyl-pyrimidin-4-yloxy}- benzonitrile2-{1-[6-(2-Chloro-4-methoxy-phenoxy)- C 447.2 M (1.67)  5pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 422.1 B (1.66) —piperidin-1-yl]-5-methyl-pyrimidin-4-yloxy}- benzonitrile5-Fluoro-2-[1-(9H-purin-6-yl)-piperidin-4- C 331.1 C (0.80) —yloxy]-pyrimidin-4-ylamine 5-Fluoro-2-{1-[6-(4-methoxy-phenylamino)- C412.0 A (1.52)  6 pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine 2-{1-[6-(Biphenyl-2-yloxy)-pyrimidin-4-yl]- C 459.2 Y (5.79) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine4-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 438.2 C (1.50) —piperidin-1-yl]-pyrimidin-4-yloxy}-3-methoxy- benzonitrile2-{1-[6-(2,4-Difluoro-phenylamino)-pyrimidin- C 418.0 A (1.54) —4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 488.0 C (1.73) —piperidin-1-yl]-5-bromo-pyrimidin-4-yloxy}- benzonitrile2-[1-(5-Bromo-6-methoxy-pyrimidin-4-yl)- C 400.9 C (1.56) —piperidin-4-yloxy]-5-fluoro-pyrimidin-4-ylamine2-{1-[2,6-Bis-(4-methoxy-phenoxy)-pyrimidin- C 536.1 A (2.03)  74-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-(1-{6-[(4-methoxy-phenyl)-methyl- C 425.9 A (1.71)  8amino]-pyrimidin-4-yl}-piperidin-4-yloxy)- pyrimidin-4-ylamine2-{1-[4-Chloro-6-(4-methoxy-phenoxy)- C 447.8 A (1.95) —[1,3,5]triazin-2-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2-methoxy-phenylamino)- C 412.0 A (1.70) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-[4′-(4-methoxy-phenoxy)-3,4,5,6- C 412.0 C (1.49) —tetrahydro-2H-[1,2′]bipyridinyl-4-yloxy]- pyrimidin-4-ylamine3-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 408.0 C (1.70)  9piperidin-1-yl]-pyrimidin-4-yloxy}-benzonitrile4-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 408.0 C (1.75) —piperidin-1-yl]-pyrimidin-4-yloxy}-benzonitrile5-Fluoro-2-{1-[6-(pyridin-2-yloxy)-pyrimidin-4- C 384.0 S (1.35) —yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(pyridin-3-yloxy)-pyrimidin-4- C 384.0 S (1.56) —yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(1H-indol-6-yloxy)-pyrimidin- C 422.0 S (1.91) —4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine2-{1-[6-(3-Bromo-phenoxy)-pyrimidin-4-yl]- C 462.8 S (2.47) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(3-phenoxy-phenoxy)- C 475.0 S (2.59) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine4-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 426.1 U (1.75) 10piperidin-1-yl]-pyrimidin-4-yloxy}-benzamide4-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 441.0 U (2.02) —piperidin-1-yl]-pyrimidin-4-yloxy}-benzoic acid methyl ester5-Fluoro-2-{1-[6-(quinolin-8-yloxy)-pyrimidin- C 434.0 U (1.76) —4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(1H-indol-4-yloxy)-pyrimidin- C 422.0 U (1.84) —4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 438.2 L (2.75) —piperidin-1-yl]-pyrimidin-4-yloxy}-5-methoxy- benzonitrile2-{1-[6-(4-Ethoxy-phenoxy)-pyrimidin-4-yl]- C 427.1 C (2.05) 11piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 426.0 C (2.07) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}- benzonitrile2-{1-[4-Chloro-6-(2-methoxy-phenoxy)- C 446.9 P (1.81) —pyrimidin-2-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine5-Fluoro-2-{1-[4-(4-methoxy-phenoxy)- C 414.0 A (1.67) 12[1,3,5]triazin-2-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine4-(4-(4-amino-5-fluoropyrimidin-2- C 428.2 V (1.56) 13yloxy)piperidin-1-yl)-6-(2- methoxyphenoxy)pyrimidin-2-amine4-(4-(4-amino-5-fluoropyrimidin-2- C 456.2 V (1.96) 14yloxy)piperidin-1-yl)-6-(2-methoxyphenoxy)-N,N-dimethylpyrimidin-2-amine 5-Fluoro-2-{1-[4-methoxy-6-(4-methoxy- C444.0 A (1.83) — phenoxy)-[1,3,5]triazin-2-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-((R)-indan-1-yloxy)-pyrimidin- C 423.0 L (3.22) —4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine2-{1-[6-(2,2-Dimethyl-2,3-dihydro-benzofuran- C 453.0 L (2.95) 157-yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4-ylamine2-{1-[6-(5-Chloro-pyridin-3-yloxy)-pyrimidin-4- C 418.0 S (2.14) 16yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(3-Amino-phenoxy)-pyrimidin-4-yl]- C 398.0 S (1.93) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(2-piperidin-1-yl-phenoxy)- C 466.0 V (2.28) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(2-morpholin-4-yl-phenoxy)- C 468.0 V (1.78) 17pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-(1-Benzo[4,5]furo[3,2-d]pyrimidin-4-yl- C 381.0 B (1.46) —piperidin-4-yloxy)-5-fluoro-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(1H-indol-7-yloxy)-pyrimidin- C 422.0 L (2.71) —4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine2-{1-[6-(1-Chloro-isoquinolin-4-yloxy)- C 468.0 S (2.39) —pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine2-(1-{6-[1-(1-Chloro-isoquinolin-4-yloxy)- C 611.0 S (2.82) —isoquinolin-4-yloxy]-pyrimidin-4-yl}-piperidin-4-yloxy)-5-fluoro-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(1H-indol-5-yloxy)-pyrimidin- C 422.0 L (2.48) —4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(3-methoxy-naphthalen-2- C 463.0 L (3.10) —yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2-methyl-quinolin-8-yloxy)- C 448.0 L (2.53) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine[4-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 443.0 Y (2.18) —piperidin-1-yl]-6-(4-methoxy-phenoxy)- [1,3,5]triazin-2-yl]-methyl-amine5-Fluoro-2-{1-[6-(3-fluoro-phenoxy)-pyrimidin- C 401.0 S (2.25) 184-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(3-trifluoromethyl-phenoxy)- C 451.0 S (2.43) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(2-fluoro-6-methoxy- C 431.1 B (1.74) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2-methoxy-4-methyl- C 427.1 B (1.78) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine2-{1-[6-(2,6-Dimethoxy-phenoxy)-pyrimidin-4- C 443.1 A (1.62) —yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(2,3-Dimethoxy-phenoxy)-pyrimidin-4- C 443.0 A (1.67) —yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine6-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 458.0 L (3.02) —piperidin-1-yl]-pyrimidin-4-yloxy}-naphthalene- 2-carbonitrile5-Fluoro-2-{1-[6-(2-methyl-benzothiazol-5- C 454.2 L (2.61) —yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2-methyl-quinolin-6-yloxy)- C 448.0 L (2.53) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-{1-[4-Chloro-6-(2-methoxy-phenoxy)- C 448.2 A (1.96) 19[1,3,5]triazin-2-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine5-Fluoro-2-{1-[2-methoxy-6-(4-methoxy- C 443.2 A (1.76) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2-pyrrol-1-yl-phenoxy)- C 448.0 V (2.34) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(7-methoxy-naphthalen-2- C 462.9 L (3.12) —yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine8-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 449.0 L (2.27) —piperidin-1-yl]-pyrimidin-4-yloxy}-quinolin-2- ylamine5-Fluoro-2-{1-[6-(6-methoxy-naphthalen-2- C 462.9 L (3.09) —yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine2-{1-[5-Bromo-6-(2-bromo-phenoxy)-pyrimidin- C 541.0 A (2.02) 204-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(Benzo[1,3]dioxol-5-yloxy)-pyrimidin- C 427.0 U (2.04) —4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine4-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 429.0 A (1.53) —piperidin-1-yl]-6-(2-methoxy-phenoxy)- [1,3,5]triazin-2-ylamine5-Fluoro-2-{1-[6-(1,2,3,4-tetrahydro-naphthalen- C 437.0 E (3.31) —1-yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(quinolin-6-yloxy)-pyrimidin- C 433.9 E (2.42) —4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[2-fluoro-6-(4-methoxy- C 431.1 A (1.89) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-fluoro-2-(4-methoxy- C 431.1 A (1.92) 21phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(4-methoxy- C 431.1 A (1.92) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine2-{1-[6-(3,4-Dimethoxy-phenoxy)-pyrimidin-4- C 443.1 A (1.57) —yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[3-(4-Chloro-pyrimidin-2-yloxy)-4- C 446.9 U (2.34) —methoxy-phenyl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine2-{1-[2-Chloro-6-(2-methoxy-phenoxy)- C 446.9 U (2.42) —pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2-methoxy-phenoxy)-2- C 489.0 X (2.72) —phenyl-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine4-(4-(4-amino-5-fluoropyrimidin-2- C 483.0 U (1.78) —yloxy)piperidin-1-yl)-6-(2- morpholinophenoxy)pyrimidin-2-amine5-Fluoro-2-{1-[6-(4-methoxy-cyclohexyloxy)- C 419.0 J (4.19) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(pyridin-4-yloxy)-pyrimidin-4- C 384.0 S (1.60) —yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-((1R,2R)-1,7,7-trimethyl- C 443.0 L (3.83) —bicyclo[2.2.1]hept-2-yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine2-{1-[6-(2-tert-Butyl-phenoxy)-pyrimidin-4-yl]- C 439.6 A (2.00) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(quinolin-7-yloxy)-pyrimidin- C 434.1 N (1.74) —4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine1-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 434.0 S (1.80) —piperidin-1-yl]-pyrimidin-4-yl}-1H-quinolin-4- one5-Fluoro-2-{1-[6-(quinolin-4-yloxy)-pyrimidin- C 434.0 S (2.08) —4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(pyridin-3-yloxy)- C 402.0 S (2.01) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-{1-[6-(4-Bromo-phenoxy)-pyrimidin-4-yl]- C 460.8 S (2.43) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- and ylamine 462.83-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 447.9 L (3.20) —piperidin-1-yl]-pyrimidin-4-yloxy}-benzofuran- 2-carbonitrile5-Fluoro-2-{1-[6-(4-fluoro-phenoxy)-pyrimidin- C 401.0 Y (2.18) —4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine2-{1-[6-(2-Chloro-5-methoxy-phenoxy)- C 447.5 U (2.28) 22pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(3-morpholin-4-yl-phenoxy)- C 468.6 U (2.00) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[2-fluoro-6-(4-methoxy- C 445.1 B (2.34) —phenoxy)-5-methyl-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine 5-Fluoro-2-{1-[6-(2-fluoro-4-methoxy- C 431.5B (1.88) — phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine 5-Fluoro-2-{1-[6-(6,7,8,9-tetrahydro- C 447.0 Q(5.59) — dibenzofuran-2-yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(4-thiazol-2-yl-phenoxy)- C 465.9 Z (2.16) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine3-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 437.9 Z (2.01) 23piperidin-1-yl]-pyrimidin-4-yloxy}-4-methoxy- benzonitrile2-(1-{6-[4-(2-Amino-thiazol-4-yl)-phenoxy]- C 480.9 AA (1.92) —pyrimidin-4-yl}-piperidin-4-yloxy)-5-fluoro- pyrimidin-4-ylamine2-[1-(6-Benzyloxy-pyrimidin-4-yl)-piperidin-4- C 397.0 L (2.90) —yloxy]-5-fluoro-pyrimidin-4-ylamine3-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 408.9 S (2.07) —piperidin-1-yl]-pyrimidin-4-yloxy}-pyridine-2- carbonitrile5-Fluoro-2-{1-[6-(3-piperidin-4-yl-phenoxy)- C 466.0 L (2.16) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine3-(1-{6-[4-(4-Amino-5-fluoro-pyrimidin-2- C 466.0 L (2.59) —yloxy)-piperidin-1-yl]-pyrimidin-4-yl}- piperidin-4-yl)-phenol3-(6-(4-(4-amino-5-fluoropyrimidin-2- C 463.9 Q (4.97) —yloxy)piperidin-1-yl)pyrimidin-4- yloxy)benzo[b]thiophene-2-carbonitrile2-(1-(6-amino-2-(4-methoxyphenoxy)pyrimidin- C 428.0 A (1.61) —4-yl)piperidin-4-yloxy)-5-fluoropyrimidin-4- amine5-Fluoro-2-[2′-(4-methoxy-phenoxy)-3,4,5,6- C 412.5 A (1.44) 24tetrahydro-2H-[1,4′]bipyridinyl-4-yloxy]- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-((1S,2S)-2-morpholin-4-yl- C 460.0 L (2.30) —cyclopentyloxy)-pyrimidin-4-yl]-piperidin-4- yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2-fluoro-benzyloxy)- C 414.9 L (2.78) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(2-methoxy-cyclohexyloxy)- C 419.0 L (2.73) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-{1-[6-(5-Chloro-pyridin-3-yloxy)-5-fluoro- C 435.9 S (2.33) —pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine5-Fluoro-2-[1-(6-piperidin-1-yl-pyrimidin-4-yl)- C 374.0 L (2.52) —piperidin-4-yloxy]-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2-trifluoromethyl-phenoxy)- C 450.9 S (2.38) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-[3′-(6-Chloro-pyrimidin-4-yloxy)-3,4,5,6- C 417.9 S (2.05) —tetrahydro-2H-[1,2′]bipyridinyl-4-yloxy]-5- fluoro-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2-iodo-pyridin-3-yloxy)- C 509.8 S (2.11) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(quinolin-3-yloxy)-pyrimidin- C 433.9 S (2.15) —4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine4-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 425.9 R (2.61) —piperidin-1-yl]-pyrimidin-4-yloxy}-2-fluoro- benzonitrile2-{1-[6-(Benzothiazol-2-yloxy)-pyrimidin-4-yl]- C 439.9 L (2.67) 25piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine3-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 425.9 S (2.38) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}- benzonitrile2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 456.1 A (1.83) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}-5- methoxy-benzonitrile2-{1-[6-(2-Chloro-4-methoxy-phenoxy)-5- C 464.9 S (2.53) —fluoro-pyrimidin-4-yl]-piperidin-4-yloxy}-5- fluoro-pyrimidin-4-ylamine3-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 455.9 S (2.34) 26piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}-4- methoxy-benzonitrile5-Fluoro-2-{1-[5-fluoro-6-(2-methoxy- C 431.0 B (1.99) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine2-[1-(6-Dimethylamino-pyrimidin-4-yl)- C 334.2 L (2.00) —piperidin-4-yloxy]-5-fluoro-pyrimidin-4-ylamine2-((6-(4-(4-amino-5-fluoropyrimidin-2- C 422.1 L (2.80) 27yloxy)piperidin-1-yl)pyrimidin-4- yloxy)methyl)benzonitrile2-{1-[6-(Biphenyl-2-ylmethoxy)-pyrimidin-4- C 473.0 L (3.52) —yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(2-methyl-4-trifluoromethyl- C 454.9 L (2.91) —2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(4-phenyl-thiazol-2-yloxy)- C 465.9 L (3.42) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-(1-{6-[2-(1H-pyrazol-3-yl)- C 449.0 V (2.55) —phenoxy]-pyrimidin-4-yl}-piperidin-4-yloxy)- pyrimidin-4-ylamine2-(1-{6-[4-(4-Amino-5-fluoro-pyrimidin-2- C 449.0 V (1.87) —yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-1H- pyrazol-3-yl)-phenol5-Fluoro-2-{1-[6-((1R,2S)-2-phenyl- C 465.0 L (3.59) —cyclohexyloxy)-pyrimidin-4-yl]-piperidin-4- yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2-[1,3,4]oxadiazol-2-yl- C 451.0 V (1.85) 28phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(4-fluoro-phenoxy)- C 418.9 U (2.39) 29pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(4-methoxy-phenoxy)-2,5- C 441.0 A (2.05) 30dimethyl-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(2-fluoro-phenoxy)- C 419.0 A (1.95) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine4-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 425.9 A (1.84) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}- benzonitrile2-{1-[6-(2,5-Dimethyl-2H-pyrazol-3-yloxy)- C 401.0 L (2.22) 31pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2-isoxazol-5-yl-phenoxy)- C 449.9 V (1.97) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[5-fluoro-6-(3-fluoro-phenoxy)- C 419.0 S (2.47) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-{1-[6-(3-Chloro-phenoxy)-5-fluoro-pyrimidin- C 434.9 S (2.61) —4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-{1-[5-fluoro-6-(3-methoxy- C 430.9 S (2.41) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine2-{1-[6-(Benzothiazol-2-yloxy)-5-fluoro- C 457.9 L (2.95) —pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-((1S,2S)-2- C 477.9 L (2.60) —morpholin-4-yl-cyclopentyloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(2-methyl- C 471.9 L (2.96) —benzothiazol-5-yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine 5-Fluoro-2-{1-[6-((1R,2S)-2-phenyl- C 451.0L (3.41) 32 cyclopentyloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine2-{1-[6-(3,4-Difluoro-phenoxy)-pyrimidin-4-yl]- C 418.9 A (1.85) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(3-Chloro-4-fluoro-phenoxy)-pyrimidin- C 434.9 R (2.93) 334-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(4-Ethoxy-phenoxy)-5-fluoro-pyrimidin- C 444.9 S (2.50) —4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-{1-[5-fluoro-6-(2-methoxy-4-methyl- C 444.9 S (2.47) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-(1-{5-fluoro-6-[1-(4-methoxy- C 499.0 U (2.27) —phenyl)-1H-tetrazol-5-yloxy]-pyrimidin-4-yl}-piperidin-4-yloxy)-pyrimidin-4-ylamine2-{1-[6-(2-Cyclohexyl-phenoxy)-pyrimidin-4- C 465.1 V (2.81) —yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(2,3-Dihydro-indol-1-yl)-pyrimidin-4- C 408.0 V (2.37) 34yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(5-methoxy-1H- C 453.0 L (2.49) —benzoimidazol-2-yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine3-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 435.9 L (1.66) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}- isoxazole-5-carboxylic acid5-Fluoro-2-{1-[5-fluoro-6-(1H-indol-2-yloxy)- C 439.9 L (2.91) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(isoquinolin-6-yloxy)- C 433.9 L (2.47) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine1-(3-{6-[4-(4-Amino-5-fluoro-pyrimidin-2- C 481.9 L (3.13) —yloxy)-piperidin-1-yl]-5-fluoro-pyrimidin-4- yloxy}-indol-1-yl)-ethanone5-fluoro-2-(1-(5-fluoro-6-(6- C 469.9 S (2.46) —(trifluoromethyl)pyridin-3-yloxy)pyrimidin-4-yl)piperidin-4-yloxy)pyrimidin-4-amine2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 443.9 S (2.41) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}-6- fluoro-benzonitrile2-{1-[6-(2-Cyclopentyl-phenoxy)-pyrimidin-4- C 451.0 V (2.62) —yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine4-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 444.0 V (1.76) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}- benzamide2-{1-[6-(2-Chloro-phenoxy)-5-fluoro-pyrimidin- C 434.9 V (2.48) —4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(2-Ethoxy-phenoxy)-5-fluoro-pyrimidin- C 444.9 V (2.41) —4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine4-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 480.5 A (1.41) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}- benzenesulfonamide5-Fluoro-2-{1-[5-fluoro-6-(4-methoxy- C 499.1 A (1.95) —phenoxy)-2-trifluoromethyl-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 436.0 S (2.59) 35piperidin-1-yl]-6-(4-methoxy-phenoxy)- benzonitrile2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 436.0 S (2.56) —piperidin-1-yl]-6-(2-methoxy-phenoxy)- benzonitrile5-Fluoro-2-(1-{6-[2-(2-methoxy-phenyl)- C 441.0 L (3.07) —ethoxy]-pyrimidin-4-yl}-piperidin-4-yloxy)- pyrimidin-4-ylamine2-{1-[6-(2-Bromo-4-methoxy-phenoxy)-5- C 508.8 S (2.55) —fluoro-pyrimidin-4-yl]-piperidin-4-yloxy}-5- andfluoro-pyrimidin-4-ylamine 510.85-Fluoro-2-{1-[6-(1-methyl-5-trifluoromethyl- C 455.0 L (2.78) —1H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 426.1 V (1.90) —piperidin-1-yl]-pyrimidin-4-yloxy}-benzamide5-Fluoro-2-{1-[5-fluoro-6-(2-fluoro-4-methoxy- C 449.5 A (1.86) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine1-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 435.5 A (1.17) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yl}- piperidine-4-carboxylic acidamide 6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 463.5 A (2.00) —piperidin-1-yl]-5-chloro-4-(4-methoxy- phenoxy)-1H-pyrimidin-2-one5-Fluoro-2-{1-[5-fluoro-6-(4-methoxy-piperidin- C 422.5 A (1.58) —1-yl)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine1-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 417.5 A (1.53) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yl}- piperidine-4-carbonitrile2-(1-(6-(4-methoxyphenoxy)pyrimidin-4- C 395.0 A (1.11) 36yl)piperidin-4-yloxy)pyrimidin-4-amine3-{6-[4-(4-Amino-pyrimidin-2-yloxy)-piperidin- C 420.1 A (1.09) 371-yl]-pyrimidin-4-yloxy}-4-methoxy- benzonitrile5-Fluoro-2-{1-[3-(4-methoxy-phenoxy)-2-nitro- C 455.9 S (2.68) 38phenyl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(6-trifluoromethyl- C 470.9 L (2.65) —pyrimidin-4-yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(4-fluoro-piperidin-1- C 410.5 A (1.68) —yl)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine2-{1-[6-(4,4-Difluoro-piperidin-1-yl)-5-fluoro- C 428.5 A (1.79) —pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine5-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 469.9 L (2.50) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}-3,4-dihydro-1H-quinolin-2-one 6-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)-C 470.0 L (2.43) — piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}-3,4-dihydro-1H-quinolin-2-one 5-Fluoro-2-{1-[6-(4-imidazol-1-yl-phenoxy)- C449.0 V (1.83) — pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(4-[1,2,4]triazol-1-yl- C 450.0 V (1.79) 39phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(2-fluoro-6-methoxy- C 448.9 S (2.42) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine2-{1-[6-(2-Chloro-5-methoxy-phenoxy)-5- C 465.1 Y (2.61) 40fluoro-pyrimidin-4-yl]-piperidin-4-yloxy}-5- fluoro-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2,2,2-trifluoro-ethoxy)- C 389.1 W (2.02) 41pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-[1-(6-Ethoxy-pyrimidin-4-yl)-piperidin-4- C 335.1 W (1.49) —yloxy]-5-fluoro-pyrimidin-4-ylamine3-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 456.1 W (2.14) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}-2- methoxy-benzonitrile2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 407.0 S (2.31) 423,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′- yloxy]-benzonitrile2-{1-[6-(2,6-Dimethoxy-phenoxy)-5-fluoro- C 461.0 S (2.34) —pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(2-methoxy-6-methyl- C 445.0 S (2.45) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(2-methoxy-5-methyl- C 445.0 S (2.48) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine2-(2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2- C 443.0 V (1.81) 43yloxy)-piperidin-1-yl]-pyrimidin-4-yloxy}- phenoxy)-ethanol3-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 441.9 S (2.23) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}-5- hydroxy-benzonitrile2-{1-[6-(2,4-Difluoro-phenoxy)-5-fluoro- C 437.0 S (2.55) —pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine3,5-Bis-{6-[4-(4-amino-5-fluoro-pyrimidin-2- C 747.9 S (2.28) —yloxy)-piperidin-1-yl]-5-fluoro-pyrimidin-4- yloxy}-benzonitrile2-[2′-(4-Ethoxy-phenoxy)-3,4,5,6-tetrahydro-2H- C 426.5 B (1.74) —[1,4′]bipyridinyl-4-yloxy]-5-fluoro-pyrimidin-4- ylamine6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 341.0 L (2.50) —piperidin-1-yl]-pyrimidine-4,5-dicarbonitrile5-Fluoro-2-{1-[5-fluoro-6-(pyren-1-yloxy)- C 525.2 A (2.14) 44pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-{1-[6-(3,5-Dimethyl-phenoxy)-5-fluoro- C 429.0 S (2.61) —pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine2-{1-[6-(3,5-Dimethoxy-phenoxy)-5-fluoro- C 461.0 S (2.19) —pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine2-{1-[6-(3,5-Difluoro-phenoxy)-5-fluoro- C 437.0 S (2.27) —pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine5-Fluoro-2-[1-(5-fluoro-6-isopropoxy-pyrimidin- C 367.2 A (2.18) —4-yl)-piperidin-4-yloxy]-pyrimidin-4-ylamine3-{6-[4-(4-Amino-pyrimidin-2-yloxy)-piperidin- C 438.0 S (2.20) 451-yl]-5-fluoro-pyrimidin-4-yloxy}-4-methoxy- benzonitrile2-{6-[4-(4-Amino-pyrimidin-2-yloxy)-piperidin- C 408.2 L (2.66) 461-yl]-5-fluoro-pyrimidin-4-yloxy}-benzonitrile2-{1-[6-(2-Chloro-4-methoxy-phenoxy)-5-nitro- C 491.9 S (2.59) —pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro- pyrimidin-4-ylamine2-{1-[5-Fluoro-6-(2-fluoro-phenoxy)-pyrimidin- C 401.0 L (2.85) —4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 453.0 S (2.41) —piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}- benzonitrile3-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 453.0 S (2.45) —piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}- benzonitrile2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 483.0 S (2.49) —piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-5- methoxy-benzonitrile5-Fluoro-2-{1-[6-(3-methoxy-phenoxy)-5-nitro- C 458.0 S (2.49) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine4-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 483.0 S (2.47) —piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-3- methoxy-benzonitrile5-Fluoro-2-{1-[6-(2-methoxy-phenoxy)-5-nitro- C 458.0 S (2.45) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-(1-{6-[4-(2-Amino-ethyl)-2-methoxy- C 474.3 R (1.85) 47phenoxy]-5-fluoro-pyrimidin-4-yl}-piperidin-4-yloxy)-5-fluoro-pyrimidin-4-ylamine2-(1-{6-[4-(2-Benzylamino-ethyl)-2-methoxy- C 564.3 R (2.47) —phenoxy]-5-fluoro-pyrimidin-4-yl}-piperidin-4-yloxy)-5-fluoro-pyrimidin-4-ylamine2-(1-{6-[4-(2-Dibenzylamino-ethyl)-2-methoxy- C 654.3 R (4.29) —phenoxy]-5-fluoro-pyrimidin-4-yl}-piperidin-4-yloxy)-5-fluoro-pyrimidin-4-ylamine2-(1-{6-[4-(2-Dimethylamino-ethyl)-2-methoxy- C 502.3 R (1.72) —phenoxy]-5-fluoro-pyrimidin-4-yl}-piperidin-4-yloxy)-5-fluoro-pyrimidin-4-ylamine2-(1-{6-[4-(2-Diethylamino-ethyl)-2-methoxy- C 530.1 A (1.48) 48phenoxy]-5-fluoro-pyrimidin-4-yl}-piperidin-4-yloxy)-5-fluoro-pyrimidin-4-ylamine2-(1-{6-[4-(2-Diethylamino-ethyl)-2-methoxy- C 512.2 R (1.70) 49phenoxy]-5-fluoro-pyrimidin-4-yl}-piperidin-4-yloxy)-pyrimidin-4-ylamine 2-{1-[6-(4-Dimethylaminomethyl-phenoxy)-5- C458.4 H (1.48) — fluoro-pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4-ylamine 2-{1-[6-(2-Dimethylaminomethyl-phenoxy)-5- C458.4 G (1.77) — fluoro-pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4-ylamine 2-{1-[6-(4-Bromo-3-dimethylaminomethyl- C538.2 G (1.99) — phenoxy)-5-fluoro-pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4-ylamine5-Fluoro-2-(1-{5-fluoro-6-[2-methoxy-4-(1H- C 499.3 G (2.56) —tetrazol-5-yl)-phenoxy]-pyrimidin-4-yl}-piperidin-4-yloxy)-pyrimidin-4-ylamine2-{1-[6-(4-Butoxy-phenoxy)-5-fluoro-pyrimidin- C 473.1 V (2.86) 504-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-{1-[5-fluoro-6-(4-hexyloxy- C 501.1 V (3.13) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine3-{6-[3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 464.1 V (2.20) —8-aza-bicyclo[3.2.1]oct-8-yl]-pyrimidin-4- yloxy}-4-methoxy-benzonitrile2-(1-{6-[4-(2-Diethylamino-ethyl)-phenoxy]-5- C 500.4 A (0.92) 51fluoro-pyrimidin-4-yl}-piperidin-4-yloxy)-5- fluoro-pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(4-methyl-piperazin- C 407.4 I (1.44) —1-yl)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamineN-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 409.4 I (1.40) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yl}-N,N′,N′-trimethyl-ethane-1,2-diamineN-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 423.4 I (1.30) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yl}-N,N′,N′-trimethyl-propane-1,3-diamine2-(4-{6-[4-(4-Amino-5-fluoro-pyrimidin-2- C 502.1 L (2.51) —yloxy)-piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}-phenoxy)-N,N-dimethyl-acetamide5-Fluoro-2-{1-[5-fluoro-6-(1-methyl-piperidin- C 422.4 G (1.51) 524-yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine3-{2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 438.3 L (2.81) 53piperidin-1-yl]-pyrimidin-4-yloxy}-4-methoxy- benzonitrile3-{4-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 438.3 L (2.44) —piperidin-1-yl]-pyrimidin-2-yloxy}-4-methoxy- benzonitrile2-{6-[3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 452.0 V (2.37) —8-aza-bicyclo[3.2.1]oct-8-yl]-5-fluoro- pyrimidin-4-yloxy}-benzonitrile4-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 453.0 S (2.44) —piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}- benzonitrile4-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- CC 437.9 X (2.25) —piperidin-1-yl]-6-(4-methoxy-phenoxy)- pyrimidine-5-carbonitrile2-(1-(2,3-dichlorophenylsulfonyl)piperidin-4- D 420.9 A (1.94) —yloxy)-5-fluoropyrimidin-4-amine 5-fluoro-2-(1-(naphthalen-1- D 403.0 A(1.93) — ylsulfonyl)piperidin-4-yloxy)pyrimidin-4-amine5-fluoro-2-(1-(naphthalen-2- D 403.3 A (1.95) —ylsulfonyl)piperidin-4-yloxy)pyrimidin-4-amine 5-fluoro-2-(1-(5- D 424.9A (1.74) — methylbenzo[c][1,2,5]thiadiazol-4-ylsulfonyl)piperidin-4-yloxy)pyrimidin-4-amine5-fluoro-2-(1-(5,5,8,8-tetramethyl-5,6,7,8- D 463.0 A (1.84) —tetrahydronaphthalen-2-ylsulfonyl)piperidin-4- yloxy)pyrimidin-4-amine5-fluoro-2-(1-(2-fluorophenylsulfonyl)piperidin- D 371.0 A (1.47) —4-yloxy)pyrimidin-4-amine 2-(1-(7-chlorobenzo[c][1,2,5]oxadiazol-4- D428.9 A (1.41) — ylsulfonyl)piperidin-4-yloxy)-5-fluoropyrimidin-4-amine 5-fluoro-2-(1-(isoquinolin-5- D 404.0 A (1.58) —ylsulfonyl)piperidin-4-yloxy)pyrimidin-4-amine5-fluoro-2-(1-(4-methylnaphthalen-1- D 417.0 A (2.02) —ylsulfonyl)piperidin-4-yloxy)pyrimidin-4-amine5-fluoro-2-(1-(4-fluoronaphthalen-1- D 421.0 A (2.02) —ylsulfonyl)piperidin-4-yloxy)pyrimidin-4-amine2-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6- D 411.0 A (1.74) —ylsulfonyl)piperidin-4-yloxy)-5-fluoropyrimidin- 4-amine2-(1-(5-(dimethylamino)naphthalen-1- D 446.0 A (2.03) —ylsulfonyl)piperidin-4-yloxy)-5-fluoropyrimidin- 4-amine5-fluoro-2-(1-(2-methoxy-4- D 397.0 A (1.70) —methylphenylsulfonyl)piperidin-4- yloxy)pyrimidin-4-amine2-(1-(5-chloro-2- D 416.9 A (1.79) —methoxyphenylsulfonyl)piperidin-4-yloxy)-5- fluoropyrimidin-4-amine2-(1-(2,5-dimethoxyphenylsulfonyl)piperidin-4- D 413.0 A (1.63) —yloxy)-5-fluoropyrimidin-4-amine 5-fluoro-2-(1-(2-(4- E 474.9 A (1.99) —methoxyphenoxy)phenylsulfonyl)piperidin-4- yloxy)pyrimidin-4-amine[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- E 439.2 A (1.73) 54piperidin-1-yl]-[2-(4-methoxy-phenoxy)- phenyl]-methanone[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- E 427.2 A (1.76) —piperidin-1-yl]-[2-(4-fluoro-phenoxy)-phenyl]- methanone6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 377.0 L (2.20) —piperidin-1-yl]-pyrimidine-4-carboxylic acid isopropyl ester6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 334.0 L (1.68) —piperidin-1-yl]-pyrimidine-4-carboxylic acid amide6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 440.0 L (3.13) —piperidin-1-yl]-pyrimidine-4-carboxylic acid (2- methoxy-phenyl)-amide{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 436.0 L (2.55) 55piperidin-1-yl]-pyrimidin-4-yl}-(2,3-dihydro- indol-1-yl)-methanone6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 424.0 L (2.16) —piperidin-1-yl]-pyrimidine-4-carboxylic acid methyl-phenyl-amide{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 450.0 L (2.44) —piperidin-1-yl]-pyrimidin-4-yl}-(3,4-dihydro-2H-quinolin-1-yl)-methanone {6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)-G 469.9 L (2.89) — piperidin-1-yl]-pyrimidin-4-yl}-(5-chloro-2,3-dihydro-indol-1-yl)-methanone{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 450.0 L (2.67) —piperidin-1-yl]-pyrimidin-4-yl}-(2-methyl-2,3-dihydro-indol-1-yl)-methanone{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 466.0 L (3.82) —piperidin-1-yl]-pyrimidin-4-yl}-(5-methoxy-2,3-dihydro-indol-1-yl)-methanone 6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)-G 454.0 L (2.27) — piperidin-1-yl]-pyrimidine-4-carboxylic acid (4-methoxy-phenyl)-methyl-amide {6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)-G 454.0 L (2.78) — piperidin-1-yl]-pyrimidin-4-yl}-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone{2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 441.0 L (3.05) —piperidin-1-yl]-thiazol-4-yl}-(2,3-dihydro-indol- 1-yl)-methanone{2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 440.9 L (2.76) —piperidin-1-yl]-thiazol-5-yl}-(2,3-dihydro-indol- 1-yl)-methanone{2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 425.1 L (2.70) 56piperidin-1-yl]-oxazol-4-yl}-(2,3-dihydro-indol- 1-yl)-methanone6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 395.1 L (2.48) —piperidin-1-yl]-5-fluoro-pyrimidine-4-carboxylic acid isopropyl ester{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 454.0 L (2.64) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yl}-(2,3-dihydro-indol-1-yl)-methanone{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 417.1 L (1.63) 57piperidin-1-yl]-pyrimidin-4-yl}-(4-methyl- piperazin-1-yl)-methanone{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- G 445.1 L (1.47) —piperidin-1-yl]-pyrimidin-4-yl}-(4-dimethylamino-piperidin-1-yl)-methanone[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- H 393.1 K (1.90) —piperidin-1-yl]-biphenyl-4-yl-methanone[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- H 367.1 A (1.67) 58piperidin-1-yl]-naphthalen-1-yl-methanone1-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- H 381.0 V (1.59) 59piperidin-1-yl]-2-(4-chloro-phenoxy)-ethanone and 383.0[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- H 481.9 V (2.24) —piperidin-1-yl]-[2-(5-phenyl-thiophen-2-yl)- thiazol-4-yl]-methanone[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- H 385 V (1.60) —piperidin-1-yl]-(3,4-dichloro-phenyl)-methanone and 387.0[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- H 351.1 V (1.51) —piperidin-1-yl]-(4-chloro-phenyl)-methanone and 353.11-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- H 347.0 V (1.53) —piperidin-1-yl]-2-phenoxy-ethanone2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 376.0 L (1.83) 60piperidin-1-yl]-N-(4-methoxy-phenyl)-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 372.1 L (1.88) 61piperidin-1-yl]-1-(2,3-dihydro-indol-1-yl)- ethanone2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 371.4 L (2.57) —piperidin-1-yl]-N-(2-cyano-phenyl)-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 396.5 L (2.39) —piperidin-1-yl]-N-naphthalen-2-yl-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 403.5 L (2.17) —piperidin-1-yl]-N-benzothiazol-5-yl-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 396.0 L (2.55) —piperidin-1-yl]-N-naphthalen-1-yl-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 403.0 L (2.53) —piperidin-1-yl]-N-benzothiazol-2-yl-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 380.1 L (2.61) —piperidin-1-yl]-N-(4-chloro-phenyl)-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 371.0 L (2.31) —piperidin-1-yl]-N-(4-cyano-phenyl)-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 371.0 L (2.28) —piperidin-1-yl]-N-(3-cyano-phenyl)-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 364.0 L (2.46) —piperidin-1-yl]-N-(2-fluoro-phenyl)-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 440.9 L (2.63) —piperidin-1-yl]-N-(2,4-dichloro-6-cyano- phenyl)-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 438.0 L (3.16) —piperidin-1-yl]-N-(2-phenoxy-phenyl)-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 438.0 L (3.06) 62piperidin-1-yl]-N-(3-phenoxy-phenyl)-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 468.0 L (2.85) —piperidin-1-yl]-N-[4-(4-methoxy-phenoxy)- phenyl]-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 346.1 L (2.24) —piperidin-1-yl]-N-phenyl-acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 415.9 L (3.14) —piperidin-1-yl]-N-(2,3-dichloro-phenyl)- acetamide1-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 396.2 L (2.78) —piperidin-1-yl]-2-(naphthalen-2-ylamino)- ethanone1-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 416.1 L (2.48) 63piperidin-1-yl]-2-[(benzo[b]thiophen-2- ylmethyl)-amino]-ethanone1-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 414.1 L (2.98) 64piperidin-1-yl]-2-(2,3-dichloro-phenylamino)- ethanone2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 402.2 L (2.61) —piperidin-1-yl]-N-benzo[b]thiophen-5-yl- acetamide2-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- I 360.2 L (2.15) 65piperidin-1-yl]-N-benzyl-acetamide5-Fluoro-2-{1-[3-(4-fluoro-phenoxy)-propyl]- J 365.4 L (2.48) 66piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[3-(4-methoxy-phenoxy)-propyl]- J 377.0 L (2.51) —piperidin-4-yloxy}-pyrimidin-4-ylamine{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- K 425.0 Y (2.04) —piperidin-1-yl]-pyrimidin-4-yl}-(4-methoxy- phenyl)-methanone2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- K 438.1 R (1.61) 67piperidin-1-yl]-pyrimidine-4-carbonyl}- benzamide3-(6-(4-(4-amino-5-fluoropyrimidin-2- K 437.9 R (2.58) —yloxy)piperidin-1-yl)-5-fluoropyrimidine-4- carbonyl)benzonitrile{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- K 442.9 R (2.57) 68piperidin-1-yl]-5-fluoro-pyrimidin-4-yl}-(4- methoxy-phenyl)-methanone{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- K 442.9 R (2.39) —piperidin-1-yl]-pyrimidin-4-yl}-(2-fluoro-4- methoxy-phenyl)-methanone{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- K 443.0 R (2.49) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yl}-(2- methoxy-phenyl)-methanone2-(1-{6-[Difluoro-(4-methoxy-phenyl)-methyl]- L 447.0 R (2.65) —pyrimidin-4-yl}-piperidin-4-yloxy)-5-fluoro- pyrimidin-4-ylamine2-(1-{6-[Difluoro-(2-fluoro-4-methoxy-phenyl)- L 465.0 R (2.76) 69methyl]-pyrimidin-4-yl}-piperidin-4-yloxy)-5- fluoro-pyrimidin-4-ylamine5-Fluoro-2-(1-{6-[fluoro-(2-fluoro-4-methoxy- L 447.5 R (2.59) 70phenyl)-methyl]-pyrimidin-4-yl}-piperidin-4- yloxy)-pyrimidin-4-ylamine{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- M 427.0 R (1.88) 71piperidin-1-yl]-pyrimidin-4-yl}-(4-methoxy- phenyl)-methanol{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- M 445.5 R (2.01) 72piperidin-1-yl]-pyrimidin-4-yl}-(2-fluoro-4- methoxy-phenyl)-methanol{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- N 440.0 R (2.03) 73[1,4′]bipiperidinyl-1′-yl]-pyrimidin-4-yl}-(4- methoxy-phenyl)-methanoneoxime {6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- N 454.0 R (2.49) 74piperidin-1-yl]-pyrimidin-4-yl}-(4-methoxy- phenyl)-methanoneO-methyl-oxime 2-(2-{6-[4-(4-Amino-5-fluoro-pyrimidin-2- O 441.0 V(1.90) — yloxy)-piperidin-1-yl]-pyrimidin-4-yloxy}- phenyl)-propan-2-ol5-Fluoro-2-(1-{6-[2-(1-methyl-1H-pyrazol-4-yl)- P 463.1 V (1.72) —phenoxy]-pyrimidin-4-yl}-piperidin-4-yloxy)- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(2-pyridin-3-yl-phenoxy)- P 460.1 O (1.74) 75pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-{1-[6-(Biphenyl-3-yloxy)-pyrimidin-4-yl]- P 459.0 S (2.59) 76piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine3′-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- P 483.9 S (2.50) —piperidin-1-yl]-pyrimidin-4-yloxy}-biphenyl-4- carbonitrile5-Fluoro-2-{1-[6-(2′-methoxy-biphenyl-3- P 488.9 S (2.58) —yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(4′-methoxy-biphenyl-3- P 488.9 S (2.56) —yloxy)-pyrimidin-4-yl]-piperidin-4-yloxy}- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(3-pyridin-4-yl-phenoxy)- P 460.0 S (2.14) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(3-pyridin-3-yl-phenoxy)- P 460.0 S (2.16) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(2-pyridin-4-yl-phenoxy)- P 460.0 V (1.95) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-{1-[6-([3,4′]Bipyridinyl-5-yloxy)-pyrimidin-4- P 460.9 S (1.90) —yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-([3,3′]Bipyridinyl-5-yloxy)-pyrimidin-4- P 460.9 S (1.90) —yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(2-pyrimidin-5-yl-phenoxy)- P 395.0 A (1.11) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-[1-(10-methylene-10H-9-oxa-1,3- P 407.0 A (1.49) 77diaza-anthracen-4-yl)-piperidin-4-yloxy]- pyrimidin-4-ylamine5-Fluoro-2-(1-{6-[3-(1-methyl-1H-pyrazol-4-yl)- P 463.0 S (2.09) —phenoxy]-pyrimidin-4-yl}-piperidin-4-yloxy)- pyrimidin-4-ylamine5-Fluoro-2-(1-{6-[3-(1H-pyrazol-4-yl)- P 449.0 S (1.97) —phenoxy]-pyrimidin-4-yl}-piperidin-4-yloxy)- pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(3-furan-2-yl-phenoxy)- P 449.0 S (2.45) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine5-Fluoro-2-{1-[6-(3-furan-3-yl-phenoxy)- P 449.0 S (2.42) —pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-{1-[6-(3-Cyclopropyl-phenoxy)-pyrimidin-4- P 423.0 S (2.43) 78yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(4-Cyclopropyl-phenoxy)-pyrimidin-4- P 423.0 S (2.45) —yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-{1-[6-(2-Cyclopropyl-phenoxy)-pyrimidin-4- P 423.0 S (2.38) —yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-[1-(5-Cyclopropyl-6-phenoxy-pyrimidin-4-yl)- P 423.0 S (2.45) —piperidin-4-yloxy]-5-fluoro-pyrimidin-4-ylamine2-{1-[5-Cyclopropyl-6-(2-cyclopropyl- P 463.0 S (2.64) —phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4-ylamine 5-Fluoro-2-(1-{5-fluoro-6-[2-(1-methyl-1H- P480.9 V (2.16) — pyrazol-4-yl)-phenoxy]-pyrimidin-4-yl}-piperidin-4-yloxy)-pyrimidin-4-ylamine5-fluoro-2-(1-(4′-methoxybiphenyl-2- P 459.1 A (2.02) —ylsulfonyl)piperidin-4-yloxy)pyrimidin-4-amine5-Fluoro-2-[1-(5-oxa-2,4-diaza- Q 407.0 A (1.63) 79dibenzo[a,d]cyclohepten-1-yl)-piperidin-4- yloxy]-pyrimidin-4-ylamine2-(1-(5-amino-6-(2-chloro-4- R 462.0 S (2.26) 80methoxyphenoxy)pyrimidin-4-yl)piperidin-4-yloxy)-5-fluoropyrimidin-4-amine2-{1-[2-Amino-3-(4-methoxy-phenoxy)-phenyl]- R 426.0 S (2.60) —piperidin-4-yloxy}-5-fluoro-pyrimidin-4- ylamine2-(1-(5-amino-6-(4-methoxyphenoxy)pyrimidin- R 428.0 S (2.11) —4-yl)piperidin-4-yloxy)-5-fluoropyrimidin-4- amine2-(1-(5-amino-6-(3-methoxyphenoxy)pyrimidin- R 428.0 S (2.14) —4-yl)piperidin-4-yloxy)-5-fluoropyrimidin-4- amine4-{5-Amino-6-[4-(4-amino-5-fluoro-pyrimidin- R 453.0 S (2.09) —2-yloxy)-piperidin-1-yl]-pyrimidin-4-yloxy}-3- methoxy-benzonitrile2-{5-Amino-6-[4-(4-amino-5-fluoro-pyrimidin- R 453.0 S (2.15) —2-yloxy)-piperidin-1-yl]-pyrimidin-4-yloxy}-5- methoxy-benzonitrile3-{5-Amino-6-[4-(4-amino-5-fluoro-pyrimidin- R 423.0 S (2.08) —2-yloxy)-piperidin-1-yl]-pyrimidin-4-yloxy}- benzonitrile2-(1-(5-amino-6-(2-methoxyphenoxy)pyrimidin- R 428.0 S (2.08) —4-yl)piperidin-4-yloxy)-5-fluoropyrimidin-4- amine4-{5-Amino-6-[4-(4-amino-5-fluoro-pyrimidin- R 423.0 S (2.06) —2-yloxy)-piperidin-1-yl]-pyrimidin-4-yloxy}- benzonitrile2-{5-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- S 396.2 A (1.27) —piperidin-1-yl]-tetrazol-2-ylmethyl}-benzonitrile2-[1-(2-Benzyl-2H-tetrazol-5-yl)-piperidin-4- S 371.0 Y (2.24) —yloxy]-5-fluoro-pyrimidin-4-ylamine5-Fluoro-2-{1-[2-(4-nitro-benzyl)-2H-tetrazol-5- S 416.0 Y (2.26) —yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-{1-[2-(4-methoxy-benzyl)-2H- S 401.0 Y (2.25) —tetrazol-5-yl]-piperidin-4-yloxy}-pyrimidin-4- ylamine2-(1-{6-[4-(2-Dimethylamino-ethoxy)-phenoxy]- T 488.1 L (2.34) —5-fluoro-pyrimidin-4-yl}-piperidin-4-yloxy)-5-fluoro-pyrimidin-4-ylamine 2-(4-{6-[4-(4-Amino-5-fluoro-pyrimidin-2- T461.0 L (2.46) 81 yloxy)-piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}-phenoxy)-ethanol 2-[1-(6-Biphenyl-4-yl-pyrimidin-4-yl)-piperidin-U 443.5 B (1.49) — 4-yloxy]-5-fluoro-pyrimidin-4-ylamine2-[1-(6-Benzo[b]thiophen-2-yl-pyrimidin-4-yl)- U 423.1 M (1.66) 82piperidin-4-yloxy]-5-fluoro-pyrimidin-4-ylamine5-Fluoro-2-{1-[6-(4′-methoxy-2′-methyl- U 487.6 B (1.21) —biphenyl-4-yl)-pyrimidin-4-yl]-piperidin-4- yloxy}-pyrimidin-4-ylamine1-(4′-{6-[4-(4-Amino-5-fluoro-pyrimidin-2- U 487.6 B (1.21) —yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-biphenyl- 4-yl)-ethanol2-[1-(6-Benzo[b]thiophen-2-yl-5-fluoro- U 441.1 L (3.50) —pyrimidin-4-yl)-piperidin-4-yloxy]-5-fluoro- pyrimidin-4-ylamine[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- V 450.1 A (1.83) —piperidin-1-yl]-(4-benzo[b]thiophen-2-yl- pyridin-2-yl)-methanone[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- V 466.9 V (2.42) —piperidin-1-yl]-(5-benzo[b]thiophen-2-yl-2- fluoro-phenyl)-methanone[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- V 508.9 V (2.36) —piperidin-1-yl]-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-methanone [4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- V470.0 N (2.29) — piperidin-1-yl]-[2-(5-methyl-benzo[b]thiophen-2-yl)-thiazol-4-yl]-methanone [4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- V447.9 N (2.22) 83 piperidin-1-yl]-[2-(4-chloro-2-methyl-phenyl)-thiazol-4-yl]-methanone [4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- V 455.9N (2.18) — piperidin-1-yl]-(2-benzo[b]thiophen-2-yl-thiazol-4-yl)-methanone [4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- V 484.9N (2.39) — piperidin-1-yl]-(4-benzo[b]thiophen-2-yl-3-methoxy-thiophen-2-yl)-methanoneN-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- W 440.0 L (2.67) 84piperidin-1-yl]-pyrimidin-4-yl}-2-methoxy- benzamide3-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- X 328.1 V (1.75) —piperidin-1-ylmethyl]-benzonitrile5-Fluoro-2-[1-(4-imidazol-1-yl-benzyl)- X 369.0 V (1.45) —piperidin-4-yloxy]-pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(2-methoxy-5- X 530.1 F (1.08) —morpholin-4-ylmethyl-phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine5-Fluoro-2-(1-{5-fluoro-6-[2-methoxy-5-(4- X 543.1 G (1.84) —methyl-piperazin-1-ylmethyl)-phenoxy]-pyrimidin-4-yl}-piperidin-4-yloxy)-pyrimidin-4- ylamine2-{1-[6-(5-Dimethylaminomethyl-2-methoxy- X 488.1 F (1.05) —phenoxy)-5-fluoro-pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4-ylamine2-{1-[6-(5-Diethylaminomethyl-2-methoxy- X 516.1 F (1.31) —phenoxy)-5-fluoro-pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(2-methoxy-4- X 530.3 G (1.84) —morpholin-4-ylmethyl-phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine2-{1-[6-(4-Cyclopropylaminomethyl-2-methoxy- X 500.2 G (1.95) —phenoxy)-5-fluoro-pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4-ylamine2-{1-[6-(4-Dimethylaminomethyl-2-methoxy- X 488.3 G (1.82) —phenoxy)-5-fluoro-pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4-ylamine5-Fluoro-2-(1-{5-fluoro-6-[2-methoxy-4-(4- X 543.3 G (1.91) —methyl-piperazin-1-ylmethyl)-phenoxy]-pyrimidin-4-yl}-piperidin-4-yloxy)-pyrimidin-4- ylamine2-{1-[6-(4-Dimethylaminomethyl-3-methoxy- X 488.1 S (2.16) 85phenoxy)-5-fluoro-pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4-ylamine5-Fluoro-2-{1-[5-fluoro-6-(3-methoxy-4- X 530.0 S (2.23) —morpholin-4-ylmethyl-phenoxy)-pyrimidin-4-yl]-piperidin-4-yloxy}-pyrimidin-4-ylamine2-{1-[6-(4-Cyclopropylaminomethyl-3-methoxy- X 498.0 S (2.29) —phenoxy)-5-fluoro-pyrimidin-4-yl]-piperidin-4-yloxy}-5-fluoro-pyrimidin-4-ylamine3-{6-[4-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- Y 456.0 S (2.18) —piperidin-1-yl]-5-fluoro-pyrimidin-4-yloxy}-5- methoxy-benzonitrile5-Fluoro-2-{(S)-1-[2-methyl-9-(tetrahydro- D 379.0 CC (1.16) —furan-2-ylmethyl)-9H-purin-6-yl]-pyrrolidin-3-yloxy}-pyrimidin-4-ylamine 2-[(R)-1-(Biphenyl-4-sulfonyl)-pyrrolidin-3-D 415.1 BB (1.63) — yloxy]-5-fluoro-pyrimidin-4-ylamine[(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- C 333.2 L (2.02) —pyrrolidin-1-yl]-acetic acid phenyl ester[(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 436.0 S (1.79) 86pyrrolidin-1-yl]-(4-benzo[b]thiophen-2-yl- pyridin-2-yl)-methanone2-[(S)-1-(5-Ethyl-pyrimidin-2-yl)-pyrrolidin-3- C 305.1 BB (1.48) —yloxy]-5-fluoro-pyrimidin-4-ylamine5-Fluoro-2-((S)-1-quinoxalin-2-yl-pyrrolidin-3- C 327.1 BB (1.68) —yloxy)-pyrimidin-4-ylamine2-[(S)-1-(4-Chloro-phthalazin-1-yl)-pyrrolidin- C 361.1 BB (1.55) —3-yloxy]-5-fluoro-pyrimidin-4-ylamine2-{(S)-1-[9-(3,4-Dimethoxy-benzyl)-2-methyl- C 481.2 BB (2.05) —9H-purin-6-yl]-pyrrolidin-3-yloxy}-5-fluoro- pyrimidin-4-ylamine1-[(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 347.1 DD (0.46) —pyrrolidin-1-yl]-2-benzyloxy-ethanone1-[(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 331.1 DD (0.48) —pyrrolidin-1-yl]-3-phenyl-propan-1-one[(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 454.0 DD (0.5) —pyrrolidin-1-yl]-[2-(2,3-dichloro-phenyl)- thiazol-4-yl]-methanone[(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 423.0 DD (0.53) —pyrrolidin-1-yl]-(5-bromo-2,3-dihydro- benzofuran-7-yl)-methanone[(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 386.1 DD (0.61) —pyrrolidin-1-yl]-(2-phenyl-thiazol-4-yl)- methanone[(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 428.1 DD (0.71) —pyrrolidin-1-yl]-[2-(2,3-dihydro-benzofuran-5-yl)-thiazol-4-yl]-methanone (S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)-D 410.2 DD (0.77) — pyrrolidine-1-carboxylic acid (4-phenoxy-phenyl)-amide (S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 368.1 DD(0.68) — pyrrolidine-1-carboxylic acid naphthalen-2- ylamide(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 394.2 DD (0.78) —pyrrolidine-1-carboxylic acid biphenyl-4- ylamide(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 346.2 DD (0.56) —pyrrolidine-1-carboxylic acid phenethyl-amide(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 324.2 DD (0.55) —pyrrolidine-1-carboxylic acid cyclohexylamide(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 361.2 DD (0.51) —pyrrolidine-1-carboxylic acid (4-dimethylamino- phenyl)-amide5-Fluoro-2-((S)-1-phenylmethanesulfonyl- C 353.1 DD (0.60) —pyrrolidin-3-yloxy)-pyrimidin-4-ylamine5-Fluoro-2-[(S)-1-(3-trifluoromethyl- D 407.1 DD (0.77) —benzenesulfonyl)-pyrrolidin-3-yloxy]-pyrimidin- 4-ylamine2-[(S)-1-(2,3-Dichloro-benzenesulfonyl)- D 407.0 DD (0.78) —pyrrolidin-3-yloxy]-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-[(S)-1-(5-fluoro-2-methyl- D 371.1 DD (0.72) —benzenesulfonyl)-pyrrolidin-3-yloxy]-pyrimidin- 4-ylamine5-Fluoro-2-[(S)-1-(toluene-3-sulfonyl)- D 353.1 DD (0.66) —pyrrolidin-3-yloxy]-pyrimidin-4-ylamine 5-Fluoro-2-[(S)-1-(4-isopropyl-D 381.1 DD (0.84) — benzenesulfonyl)-pyrrolidin-3-yloxy]-pyrimidin-4-ylamine 2-[(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 364.1 DD(0.57) — pyrrolidine-1-sulfonyl]-benzonitrile5-Fluoro-2-[(S)-1-(4-fluoro-benzenesulfonyl)- D 357.1 DD (0.62) —pyrrolidin-3-yloxy]-pyrimidin-4-ylamine5-Fluoro-2-[(S)-1-(naphthalene-1-sulfonyl)- D 389.1 DD (0.76) —pyrrolidin-3-yloxy]-pyrimidin-4-ylamine 5-Fluoro-2-[(S)-1-((E)-2-phenyl-D 365.1 DD (0.69) — ethenesulfonyl)-pyrrolidin-3-yloxy]-pyrimidin-4-ylamine 5-Fluoro-2-[(S)-1-(4-phenoxy-benzenesulfonyl)- D 431.1 DD(0.89) — pyrrolidin-3-yloxy]-pyrimidin-4-ylamine5-Fluoro-2-((S)-1-naphthalen-2-ylmethyl- X 339.2 DD (0.48) —pyrrolidin-3-yloxy)-pyrimidin-4-ylamine 2-[(S)-1-((1R,5S)-6,6-Dimethyl-X 333.2 DD (0.53) — bicyclo[3.1.1]hept-2-en-2-ylmethyl)-pyrrolidin-3-yloxy]-5-fluoro-pyrimidin-4-ylamine5-Fluoro-2-((S)-1-pyridin-4-ylmethyl-pyrrolidin- X 290.1 DD (0.18) —3-yloxy)-pyrimidin-4-ylamine2-[(S)-1-(4-Dimethylamino-benzyl)-pyrrolidin- X 332.2 DD (0.26) —3-yloxy]-5-fluoro-pyrimidin-4-ylamine5-Fluoro-2-[(S)-1-(4-methoxy-benzyl)- X 319.1 DD (0.37) —pyrrolidin-3-yloxy]-pyrimidin-4-ylamine5-Fluoro-2-[(S)-1-(4-trifluoromethoxy-benzyl)- X 373.1 DD (0.51) —pyrrolidin-3-yloxy]-pyrimidin-4-ylamine2-((S)-1-Biphenyl-4-ylmethyl-pyrrolidin-3- X 365.2 DD (0.57) —yloxy)-5-fluoro-pyrimidin-4-ylamine2-((S)-1-Benzofuran-2-ylmethyl-pyrrolidin-3- X 329.1 DD (0.42) —yloxy)-5-fluoro-pyrimidin-4-ylamine5-Fluoro-2-[(S)-1-(3-phenoxy-benzyl)- X 381.2 DD (0.57) —pyrrolidin-3-yloxy]-pyrimidin-4-ylamine2-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-6- X 347.1 DD (0.37) —ylmethyl)-pyrrolidin-3-yloxy]-5-fluoro- pyrimidin-4-ylamine5-Fluoro-2-[(S)-1-(3-phenyl-butyl)-pyrrolidin-3- X 331.2 DD (0.49) —yloxy]-pyrimidin-4-ylamine 1-{4′-[(S)-3-(4-Amino-5-fluoro-pyrimidin-2- X407.2 DD (0.52) — yloxy)-pyrrolidin-1-ylmethyl]-biphenyl-3-yl}- ethanone2-[(S)-1-(4-Benzyloxy-3-methoxy-benzyl)- X 425.2 DD (0.58) —pyrrolidin-3-yloxy]-5-fluoro-pyrimidin-4- ylamine5-Fluoro-2-[(S)-1-(2,3,4-trimethoxy-benzyl)- X 379.2 DD (0.41) —pyrrolidin-3-yloxy]-pyrimidin-4-ylamine2-[(S)-1-(4′-Chloro-biphenyl-3-ylmethyl)- X 399.1 DD (0.64) —pyrrolidin-3-yloxy]-5-fluoro-pyrimidin-4- ylamine2-[(S)-1-(3′,4′-Dimethyl-biphenyl-2-ylmethyl)- X 393.2 DD (0.64) —pyrrolidin-3-yloxy]-5-fluoro-pyrimidin-4- ylamine2-[(S)-1-(3-Cyclopentyloxy-4-methoxy-benzyl)- X 403.2 DD (0.52) —pyrrolidin-3-yloxy]-5-fluoro-pyrimidin-4- ylamine(S)-3-(4-Amino-5-fluoro-pyrimidin-2-yloxy)- D 449.8 L (3.14) —pyrrolidine-1-carboxylic acid (3- benzo[b]thiophen-2-yl-phenyl)-amide4-Amino-5-fluoro-1-{1-[6-(4-methoxy- C 427.5 A (1.63) —phenoxy)-pyrimidin-4-yl]-azepan-4-yl}-1H- pyrimidin-2-one

¹H NMR data for certain compounds listed above are provided in Table 3:

TABLE 3 1 (300 MHz, DMSO-d6) δ ppm: 8.43 (s, 1H) 7.88 (s, 1H) 7.75-7.70(m, 4H) 7.27 (d, J = 9.2 Hz, 1H) 5.20-5.12 (m, 1H) 4.02-3.92 (m, 2H)3.75 (s, 3H) 3.60-3.49 (m, 2H) 2.06-1.95 (m, 2H) 1.74-1.61 (m, 2H) 2(400 MHz, MeOD-d4) δ ppm: 1.73-1.76 (m, 2H) 1.98-2.06 (m, 2H) 3.54-3.67(m, 2H) 3.92 (s, 2H) 3.97-4.03 (m, 2H) 5.13-5.19 (m, 1H) 6.69 (s, 1H)7.20-7.32 (m, 5H) 7.82 (d, J = 3.32 Hz, 1H) 8.37 (d, J = 0.98 Hz, 1H) 3(300 MHz MeOD-d4) δ ppm: 1.15 (t, 6 Hz, 3H), 1.67 (m, 2H), 1.91 (m, 2H),2.58 (q, 9.0 Hz, 8.0 Hz, 2H), 3.44 (m, 2H), 3.82 (m, 2H), 5.05 (m, 1H),5.94 (s, 1H), 6.93 (m, 2H), 1.17 (m, 2H), 7.72 (d, 6.0 Hz, 1H, 8.06 (s,1H) 4 (400 MHz MeOD-d4) δ ppm: 1.76 (m, 2H), 2.02 (m, 2H), 3.53 (m, 2H),3.91 (m, 2H), 5.15 (m, 1H), 6.99 (m, 1H), 7.11 (m, 2H), 7.25 (m, 1H)7.82 (d, 3.6 Hz, 1H), 8.10 (d, 0.8 Hz, 1H) 5 (400 MHz MeOD-d4) δ ppm:1.77 (m, 2H), 2.04 (m, 2H), 3.56 (m, 2H), 3.82 (s, 3H), 3.95 (m, 2H),5.16 (m, 1H), 6.099 d, 0.8 Hz, 1H), 6.93 (d, 8.8 Hz, 1H), 7.07 (d, 2.8hz, 1H), 7.14 (d, 8.4 Hz, 1H), 7.82 (d, 3.2 Hz, 1H), 8.12 (d, 0.8 Hz,1H) 6 (400 MHz, MeOD-d4) δ ppm: 1.69-1.78 (m, 2H) 1.99 (br. s., 2H)3.38-3.45 (m, 2H) 3.79 (s, 3H) 3.83 (s, 2H) 5.09-5.15 (m, 1H) 5.82 (d, J= 0.98 Hz, 1H) 6.89-6.93 (m, 2H) 7.24-7.28 (m, 2H) 7.81 (d, J = 3.32 Hz,1H) 8.05 (d, J = 0.78 Hz, 1H) 7 (400 MHz, MeOD-d4) δ ppm: 1.64 (m, 2H),1.91 (m, 2H), 3.32 (m, 2H), 3.72 (m, 2H), 3.77 (s, 3H), 3.79 (s, 3H),5.06 (m, 1H), 5.06 (s, 1H), 6.91 (m, 4H), 7.02 (m, 4H), 7.79 (d, 3.6 Hz,1H) 8 (400 MHz, MeOD-d4) δ ppm: 1.62-1.72 (m, J = 8.43, 8.43, 4.49, 4.25Hz, 2H) 1.91-2.00 (m, 2H) 3.25-3.33 (m, 2H) 3.35 (s, 3H) 3.71-3.79 (m,2H) 3.82 (s, 3H) 5.04-5.11 (m, 1H) 5.45 (s, 1H) 7.01 (d, J = 8.99 Hz,2H) 7.17 (d, J = 8.79 Hz, 2H) 7.79 (d, J = 3.32 Hz, 1H) 8.08 (s, 1H) 9(400 MHz, MeOD-d4) δ ppm: 1.74-1.83 (m, 2H) 2.01-2.08 (m, 2H) 3.56-3.64(m, 2H) 3.95-4.03 (m, 2H) 5.14-5.20 (m, J = 7.35, 7.35, 3.57, 3.42 Hz,1H) 6.29 (s, 1H) 7.42-7.47 (m, J = 9.67, 4.05, 3.76, 2.83 Hz, 1H)7.53-7.55 (m, 1H) 7.59 (ddd, J = 3.57, 1.71, 1.56 Hz, 2H) 7.82 (d, J =3.32 Hz, 1H) 8.17 (d, J = 0.78 Hz, 6H) 10 (400 MHz, DMSO-d6) δ ppm: 8.18(s, 1H) 7.97-7.91 (m, 2H) 7.89 (d, J = 8.0 Hz, 2H) 7.34 (s, 1H) 7.25 (s,2H) 7.17 (d, J = 8.0 Hz, 2H) 6.42 (s, 1H) 5.08-5.00 (m, 1H) 4.04-3.87(m, 2H) 3.50-3.40 (m, 2H) 2.01-1.91 (m, 2H) 1.65-1.54 (m, 2H) 11 (300MHz, CDCl₃) δ ppm: 1.44 (t, J = 6.96 Hz, 3H) 1.73-2.16 (m, 4H) 3.51-3.99(m, 4H) 4.05 (q, J = 6.87 Hz, 2H) 5.09 (br. s., 2H) 5.12-5.23 (m, 1H)5.91 (s, 1H) 6.99 (dd, 2H) 7.92 (d, J = 2.67 Hz, 1H) 8.35 (s, 1H) 12(400 MHz, MeOD-d4) δ ppm: 1.64-1.81 (m, 2H) 1.91-2.05 (m, 2H) 3.51-3.60(m, 1H) 3.76-3.83 (m, 4H) 3.84-3.92 (m, 1H) 4.10-4.19 (m, 1H) 5.09-5.17(m, 1H) 6.92-6.98 (m, 2H) 7.05-7.11 (m, 2H) 7.81 (d, J = 3.52 Hz, 1H)8.32 (s, 1H) 13 (400 MHz, MeOH) δ ppm: 7.80 (d, J = 3.5 Hz, 2H) 7.22(ddd, J = 1.5, 7.4, 7.4 Hz, 1H) 7.11-7.06 (m, 2H) 6.97 (ddd, J = 1.5,7.6, 7.6 Hz, 1H) 5.27 (s, 1H) 5.13-5.07 (m, 1H) 3.88-3.81 (m, 2H) 3.78(s, 3H) 3.41-3.33 (m, 2H) 2.01-1.97 (m, 2H) 1.73-1.64 (m, 2H) 14 (400MHz, MeOH) δ ppm: 7.80 (d, J = 3.5 Hz, 1H) 7.20 (ddd, J = 8.2, 7.4, 1.8Hz, 1H) 7.10-7.06 (m, 2H) 6.96 (ddd, J = 1.5, 7.6, 7.6 Hz, 1H) 5.17 (s,1H) 5.12-5.06 (m, 1H) 3.92-3.83 (m, 2H) 3.77 (s, 3H) 3.39-3.31 (m, 2H)2.02-1.94 (m, 2H) 1.73-1.63 (m, 2H) 15 (400 MHz, MeOD-d4) δ ppm: 1.41(s, 6H) 1.71-1.79 (m, 2H) 1.98-2.05 (m, 2H) 3.08 (s, 2H) 3.49-3.57 (m,2H) 3.88-3.96 (m, 2H) 5.14 (tt, J = 7.42, 3.71 Hz, 1H) 5.99 (s, 1H)6.82-6.92 (m, 2H) 7.07 (dd, J = 7.23, 1.17 Hz, 1H) 7.81 (d, J = 3.52 Hz,1H) 8.13 (d, J = 0.78 Hz, 1H) 16 (300 MHz, CDCl₃) δ ppm: 1.83 (ddd, J =13.49, 6.82, 3.91 Hz, 2H) 1.96 (dd, J = 8.20, 4.20 Hz, 2H) 3.55 (ddd, J= 13.21, 3.67, 3.53 Hz, 2H) 3.88 (ddd, J = 13.02, 3.96, 3.62 Hz, 2H)5.11 (td, J = 7.01, 3.72 Hz, 1H) 5.17 (br. s., 2H) 6.02 (s, 1H) 7.48 (t,J = 2.19 Hz, 1H) 7.82 (d, J = 2.48 Hz, 1H) 8.20 (s, 1H) 8.32 (dd, J =15.74, 2.00 Hz, 2H) 17 (300 MHz, MeOH) δ ppm: 1.67-1.81 (m, 2H)1.90-2.08 (m, 2H) 2.96-3.04 (m, 4H) 3.46-3.61 (m, 6H) 3.75-3.88 (m, 1H)3.88-3.98 (m, 1H) 5.15 (tt, J = 7.41, 3.55 Hz, 1H) 5.95 (s, 1H)7.07-7.15 (m, 3H) 7.21-7.31 (m, 1H) 7.82 (d, J = 3.43 Hz, 1H) 8.17 (d, J= 0.57 Hz, 1H) 18 (300 MHz, CDCl₃) δ ppm: 1.75-1.88 (m, 2H) 1.92-2.03(m, 2H) 3.47-3.58 (m, 2H) 3.81-3.93 (m, 2H) 4.97 (br. s., 2H) 5.10 (dt,J = 7.15, 3.48 Hz, 1H) 5.95 (s, 1H) 6.78-6.90 (m, 3H) 7.23-7.33 (m, 1H)7.84 (d, J = 2.67 Hz, 1H) 8.25 (s, 1H) 19 (400 MHz, CDCl₃) δ ppm:1.80-2.03 (m, 4H) 3.65-3.75 (m, 1H) 3.79 (s, 3H) 3.83-3.94 (m, 2H)4.03-4.11 (m, 1H) 5.14 (d, J = 3.32 Hz, 3H) 6.93-7.00 (m, 2H) 7.12 (dd,J = 7.82, 1.56 Hz, 1H) 7.19-7.24 (m, 1H) 7.90 (d, J = 2.54 Hz, 1H) 20(400 MHz, MeOD-d4) δ ppm: 1.94 (br. s., 2H) 2.15 (br. s., 2H) 3.59 (br.s., 2H) 3.98 (br. s., 2H) 5.18 (br. S., 1H) 7.12-7.25 (m, 2H) 7.40 (td,J = 7.72, 1.56 Hz, 1H) 7.65 (dd, J = 7.82, 1.17 Hz, 1H) 7.78 (s, 1H)7.83 (d, J = 3.52 Hz, 1H) 21 (400 MHz, CDCl₃) δ ppm: 1.79 (s, 2H) 1.93(s, 2H) 3.49 (s, 2H) 3.74 (s, 3H) 3.74-3.84 (m, 2H) 4.96 (s, 2H) 5.07(s, 1H) 5.64 (d, J = 3.13 Hz, 2H) 6.76-6.88 (m, 2H) 6.97 (s, 2H) 7.82(d, J = 2.54 Hz, 2H) 22 (400 MHz, CDCl₃) δ ppm: 8.22 (s, 1H) 7.82 (d, J= 2.7 Hz, 1H) 7.26 (d, J = 9.5 Hz, 1H) 6.70-6.67 (m, 2H) 5.99 (s, 1H)5.17 (s, 2H) 5.13-5.05 (m, 1H) 3.92-3.89 (m, 2H) 3.71 (s, 3H) 3.56-3.47(m, 2H) 2.03-1.93 (m, 2H) 1.86-1.76 (m, 2H) 23 (400 MHz, CDCl₃) δ ppm:8.19 (s, 1H) 7.85 (d, J = 2.5 Hz, 1H) 7.49 (dd, J = 2.0, 8.5 Hz, 1H)7.35 (d, J = 1.95 Hz, 1H) 6.97 (d, J = 8.6 Hz, 1H) 6.05 (s, 1H)5.16-5.09 (m, 1H) 5.06 (s, 2H) 3.94-3.85 (m, 2H) 3.78 (s, 3H) 3.63-3.53(m, 2H) 2.04-1.95 (m, 2H) 1.90-1.81 (m, 2H) 24 (300 MHz, CDCl₃) δ ppm:1.94 (s, 2H) 2.02-2.18 (m, 2H) 3.19-3.38 (m, 2H) 3.57-3.75 (m, 2H) 3.82(s, 3H) 5.05 (br. s., 2H) 5.14 (s, 1H) 6.23 (d, J = 2.29 Hz, 1H) 6.46(dd, J = 6.10, 2.29 Hz, 1H) 6.99 (dd, 4H) 7.90 (d, J = 6.10 Hz, 1H) 7.92(d, J = 2.67 Hz, 1H) 25 (400 MHz, MeOD-d4) δ ppm: 1.92-2.01 (m, 2H)2.14-2.23 (m, 2H) 3.82 (br. s., 2H) 4.06 (br. s., 2H) 5.43-5.49 (m, 1H)7.13 (d, J = 0.78 Hz, 1H) 7.23-7.35 (m, 3H) 7.58 (d, J = 8.01 Hz, 1H)8.19 (d, J = 5.08 Hz, 1H) 8.62 (s, 1H) 26 (300 MHz, MeOH) δ ppm: 2.13(dd, J = 6.77, 3.53 Hz, 1H) 2.34 (dd, J = 13.54, 4.01 Hz, 1H) 3.33 (t, J= 2.48 Hz, 1H) 3.88-4.03 (m, 5H) 4.04-4.18 (m, 1H) 5.55 (d, J = 3.24 Hz,1H) 6.24 (br. s., 3H) 7.37 (d, J = 8.77 Hz, 1H) 7.67 (d, J = 1.91 Hz,1H) 7.75 (dd, J = 8.58, 1.91 Hz, 1H) 8.16 (s, 1H) 8.23 (d, J = 4.77 Hz,1H) 27 (400 MHz, MeOD-d4) δ ppm: 1.93-2.05 (m, 2H) 2.11-2.25 (m, 2H)3.80-3.93 (m, 2H) 3.98-4.09 (m, 2H) 5.46 (s, 3H) 6.48 (s, 1H) 7.61 (t, J= 7.82 Hz, 1H) 7.72-7.82 (m, 2H) 7.86 (s, 1H) 8.18 (d, J = 4.88 Hz, 1H)8.38 (s, 1H) 28 (300 MHz, CDCl₃) δ ppm: 1.86-1.98 (m, 2H) 2.03-2.14 (m,2H) 3.58-3.69 (m, 2H) 3.93-4.03 (m, 2H) 5.07 (br. s., 2H) 5.16-5.24 (m,J = 7.06, 7.06, 3.81, 3.62 Hz, 1H) 6.18 (s, 1H) 7.31 (d, J = 0.76 Hz,1H) 7.43 (td, J = 7.63, 1.14 Hz, 1H) 7.63 (td, J = 7.82, 1.72 Hz, 1H)7.93 (d, J = 2.67 Hz, 1H) 8.16 (dd, J = 7.92, 1.62 Hz, 1H) 8.23 (s, 1H)8.43 (s, 1H) 29 (400 MHz, DMSO-d6) δ ppm: 7.98 (s, 1H) 7.92 (d, J = 3.3Hz, 1H) 7.27-7.23 (m, 6H) 5.09-5.02 (m, 1H) 4.06-3.97 (m, 2H) 3.61-3.51(m, 2H) 2.08-1.98 (m, 2H) 1.73-1.62 (m, 2H) 30 (400 MHz, CDCl₃) δ ppm:1.93 (s, 2H) 2.09-2.14 (m, 2H) 2.16 (s, 3H) 2.35 (s, 3H) 3.21 (s, 2H)3.60-3.77 (m, 2H) 3.81 (s, 3H) 5.02 (s, 2H) 5.04-5.16 (m, 1H) 6.95 (dd,4H) 7.91 (d, J = 2.74 Hz, 1H) 31 (400 MHz, MeOD-d4) δ ppm: 1.75-1.83 (m,2H) 2.01-2.08 (m, 2H) 2.20 (s, 3H) 3.58 (s, 3H) 3.59-3.65 (m, 2H) 3.99(br. s., 2H) 5.15-5.20 (m, 1H) 5.82 (s, 1H) 6.34 (d, J = 0.78 Hz, 1H)7.82 (d, J = 3.52 Hz, 1H) 8.19 (d, J = 0.78 Hz, 1H) 32 (400 MHz,MeOD-d4) δ ppm: 1.66-1.80 (m, 3H) 1.85-1.99 (m, 5H) 2.20-2.30 (m, 2H)3.22 (ddd, J = 9.57, 8.01, 5.86 Hz, 1H) 3.34-3.45 (m, 2H) 3.75-3.88 (m,2H) 5.08-5.14 (m, 1H) 5.20 (dd, J = 5.86, 3.13 Hz, 1H) 5.84 (s, 1H)7.15-7.20 (m, 1H) 7.27 (s, 2H) 7.28 (d, J = 0.78 Hz, 2H) 7.81 (d, J =3.32 Hz, 1H) 8.10 (s, 1H) 33 (400 MHz, MeOD-d4) δ ppm: 1.73-1.82 (m, 2H)2.00-2.08 (m, 2H) 3.55-3.62 (m, 2H) 3.94-4.02 (m, 2H) 5.14-5.20 (m, 1H)6.22 (s, 1H) 7.08-7.12 (m, 1H) 7.30 (dd, J = 6.25, 2.74 Hz, 2H) 7.82 (d,J = 3.52 Hz, 1H) 8.16 (d, J = 0.78 Hz, 1H) 34 (300 MHz, CDCl₃) δ ppm:1.82-1.99 (m, 2H) 2.00-2.15 (m, 2H) 3.22 (t, J = 8.39 Hz, 2H) 3.48-3.95(m, 2H) 3.95-4.08 (m, 4H) 5.16 (tt, J = 7.30, 3.67 Hz, 1H) 5.77 (s, 1H)6.91 (t, J = 7.34 Hz, 1H) 7.17-7.24 (m, 2H) 7.92 (d, J = 2.29 Hz, 1H)8.28 (d, J = 8.20 Hz, 1H) 8.40 (s, 1H) 35 (300 MHz, CDCl₃) δ ppm:2.05-2.27 (m, 4H) 3.21-3.33 (m, 1H) 3.44-3.56 (m, 2H) 3.84 (s, 3H) 5.07(br. s., 1H) 5.17 (ddd, J = 6.29, 3.05, 2.86 Hz, 1H) 6.30 (d, J = 8.39Hz, 1H) 6.66 (d, J = 8.01 Hz, 1H) 6.89-6.98 (m, 2H) 7.02-7.10 (m, 2H)7.93 (d, J = 2.67 Hz, 1H) 36 (400 MHz, MeOD-d4) δ ppm: 1.79 (dd, J =13.09, 3.71 Hz, 2H) 1.95-2.05 (m, 2H) 3.52 (d, J = 8.40 Hz, 2H) 3.80 (s,3H) 3.85 (br. s., 2H) 5.19 (br. s., 1H) 5.84 (s, 1H) 6.11 (d, J = 5.86Hz, 1H) 6.90-6.97 (m, 2H) 6.99-7.06 (m, 2H) 7.82 (d, J = 6.06 Hz, 1H)8.17 (s, 1H) 37 (400 MHz, CDCl₃) δ ppm: 1.90 (td, J = 6.59, 3.81 Hz, 2H)2.00-2.09 (m, 2H) 3.62 (d, J = 4.49 Hz, 2H) 3.83 (br. s., 3H) 3.93 (br.s., 2H) 5.11 (br. s., 2H) 5.27 (br. s., 1H) 6.09 (s, 1H) 6.11 (d, J =5.86 Hz, 1H) 7.02 (d, J = 8.60 Hz, 1H) 7.40 (d, J = 1.95 Hz, 1H) 7.53(dd, J = 8.50, 2.05 Hz, 1H) 8.00 (d, J = 5.67 Hz, 1H) 8.22 (s, 1H) 38(300 MHz, CDCl₃) δ ppm: 1.93-2.04 (m, 2H) 2.04-2.15 (m, 2H) 2.96-3.09(m, 2H) 3.22-3.36 (m, 2H) 3.82 (s, 3H) 5.08 (br. s., 3H) 6.54 (d, J =8.20 Hz, 1H) 6.86-6.97 (m, 3H) 7.03 (d, J = 8.77 Hz, 2H) 7.20-7.34 (m,2H) 7.92 (br. s., 1H) 39 (300 MHz, MeOH) δ ppm: 1.67-1.82 (m, 2H)1.87-2.01 (m, 2H) 3.40-3.54 (m, 2H) 3.74-3.86 (m, 2H) 5.12-5.23 (m, 1H)5.92 (s, 1H) 7.15 (d, J = 8.77 Hz, 2H) 7.63 (d, J = 8.77 Hz, 2H)7.76-7.84 (m, 1H) 7.97 (s, 1H) 8.11 (s, 1H) 8.61 (br. s., 1H) 40 (400MHz, DMSO-d6) δ ppm: 7.96 (d, J = 1.0 Hz, 1H) 7.62 (d, J = 3.3 Hz, 1H)7.45 (d, J = 9.0 Hz, 1H) 7.25, (s, 2H) 6.99 (d, J = 2.9 Hz, 1H) 6.89(dd, J = 2.9, 9.0 Hz, 1H) 5.10-5.02 (m, 1H) 3.74 (s, 3H) 3.62-3.54 (m,2H) 2.09-1.99 (m, 2H) 1.73-1.63 (m, 2H) 41 (400 MHz, DMSO-d6) δ ppm:8.20 (s, 1H) 7.91 (d, J = 3.3 Hz, 1H) 7.24 (s, 2H) 6.08, (s, 1H)5.04-4.97 (m, 1H) 4.25 (q, J = 7.0 Hz, 2H) 3.95-3.87 (m, 2H) 3.41-3.33(m, 2H) 1.97-1.88 (m, 2H) 1.60-1.50 (m, 2H) 1.25 (t, J = 7.0 Hz, 3H) 42(300 MHz, CDCl₃) δ ppm: 1.39-1.66 (m, 2H) 1.84-1.98 (m, 2H) 3.03-3.18(m, 2H) 3.70-3.84 (m, 2H) 4.85 (ddd, J = 8.54, 4.48, 4.34 Hz, 1H) 4.93(br. s., 2H) 6.46 (d, J = 8.58 Hz, 1H) 6.80 (dd, J = 7.72, 4.86 Hz, 1H)7.03 (t, J = 7.63 Hz, 1H) 7.22-7.38 (m, 2H) 7.56 (d, J = 7.63 Hz, 1H)7.79 (d, J = 2.48 Hz, 1H) 8.09 (d, J = 3.24 Hz, 1H) 43 (300 MHz, MeOH) δppm: 1.71-1.85 (m, 2H) 1.97-2.10 (m, 2H) 3.48-3.61 (m, 2H) 3.70 (t, J =4.86 Hz, 2H) 3.89-4.00 (m, 2H) 4.05 (t, J = 4.96 Hz, 2H) 5.17 (tt, J =7.32, 3.46 Hz, 1H) 6.06 (s, 1H) 6.99-7.07 (m, 1H) 7.12-7.20 (m, 2H)7.20-7.29 (m, 1H) 7.84 (d, J = 3.24 Hz, 1H) 8.14 (s, 1H) 44 (400 MHz,DMSO-d6) δ ppm: 1.74 (d, J = 8.79 Hz, 2H) 2.06 (br. s., 2H) 3.64 (t, J =9.57 Hz, 2H) 4.09 (d, J = 6.64 Hz, 2H) 5.09 (br. s., 1H) 7.27 (br. s.,2H) 7.87 (d, J = 0.78 Hz, 1H) 7.91-7.96 (m, 2H) 8.05-8.14 (m, 2H) 8.20(d, J = 9.38 Hz, 3H) 8.34 (d, J = 8.60 Hz, 3H) 45 (300 MHz, DMSO-d6) δppm: 1.63-1.76 (m, 2H) 1.99-2.11 (m, 2H) 3.52-3.65 (m, 2H) 3.82 (s, 3H)3.99-4.15 (m, 2H) 5.10-5.19 (m, 1H) 6.07 (d, J = 5.72 Hz, 1H) 6.84 (br.s., 2H) 7.34 (d, J = 9.16 Hz, 1H) 7.76-7.82 (m, J = 4.53, 2.31, 2.31,2.10 Hz, 2H) 7.86 (d, J = 5.72 Hz, 1H) 7.94 (d, J = 0.76 Hz, 1H) 46 (300MHz, DMSO-d6) δ ppm: 1.73 (td, J = 8.20, 4.01 Hz, 2H) 2.06 (ddd, J =9.35, 6.58, 3.15 Hz, 2H) 3.66 (dd, J = 8.96, 3.05 Hz, 1H) 4.07 (td, J =6.72, 2.57 Hz, 2H) 5.16 (dt, J = 7.58, 3.74 Hz, 1H) 6.07 (d, J = 5.72Hz, 1H) 6.84 (br. s., 2H) 7.44-7.53 (m, 2H) 7.80 (dd, J = 16.02, 1.53Hz, 1H) 7.86 (d, J = 5.72 Hz, 1H) 7.96 (dd, J = 7.63, 1.34 Hz, 1H) 8.03(s, 1H) 47 (300 MHz, MeOH) δ ppm: 1.77-1.89 (m, 2H) 2.06-2.16 (m, 2H)2.96-3.03 (m, 2H) 3.19-3.25 (m, 2H) 3.62-3.73 (m, 2H) 3.78 (s, 3H)4.07-4.17 (m, 2H) 5.12-5.21 (m, 1H) 6.91 (dd, J = 8.11, 1.81 Hz, 1H)7.05 (d, J = 1.72 Hz, 1H) 7.10 (d, J = 8.01 Hz, 1H) 7.82-7.84 (m, 2H) 48(300 MHz, MeOH) δ ppm: 1.35 (t, J = 7.25 Hz, 6H) 1.79-1.91 (m, 2H)2.08-2.18 (m, 2H) 3.03-3.12 (m, 4H) 3.26 (q, J = 7.25 Hz, 4H) 3.64-3.73(m, 2H) 3.80 (s, 3H) 4.08-4.20 (m, 2H) 5.12-5.26 (m, 1H) 6.95 (dd, J =8.11, 1.62 Hz, 1H) 7.07-7.13 (m, 2H) 7.81-7.88 (m, 2H) 49 (300 MHz,MeOH) δ ppm: 1.31 (t, J = 7.25 Hz, 6H) 1.76-1.87 (m, 2H) 2.06-2.19 (m,2H) 2.98-3.07 (m, 2H) 3.12-3.28 (m, 6H) 3.64-3.77 (m, 2H) 3.80 (s, 3H)4.08-4.23 (m, 2H) 5.22-5.33 (m, 1H) 6.16 (d, J = 5.91 Hz, 1H) 6.94 (dd,J = 8.01, 1.91 Hz, 1H) 7.07 (d, J = 1.91 Hz, 1H) 7.10 (d, J = 8.01 Hz,1H) 7.83 (s, 1H) 7.87 (d, J = 5.91 Hz, 1H) 50 (300 MHz, CDCl₃) δ ppm:0.98 (t, J = 7.34 Hz, 3H) 1.43-1.55 (m, 3H) 1.71-1.82 (m, 2H) 1.86-1.98(m, 2H) 2.05-2.17 (m, 2H) 3.65-3.77 (m, 2H) 3.96 (t, J = 6.48 Hz, 2H)4.05-4.17 (m, 2H) 5.06 (br. s., 2H) 5.17 (tt, J = 7.32, 3.55 Hz, 1H)6.89-6.95 (m, 2H) 7.03-7.11 (m, 2H) 7.92 (d, J = 2.48 Hz, 1H) 8.01 (s,1H) 51 (400 MHz, MeOD) δ ppm: 1.34 (t, J = 7.28 Hz, 6H) 1.84 (td, J =8.53, 4.02 Hz, 2H) 1.95 (s, 3H) 2.08 (br. s., 2H) 3.01-3.11 (m, 2H) 3.26(q, J = 7.36 Hz, 4H) 3.29-3.35 (m, 2H) 3.63-3.73 (m, 2H) 4.12 (ddd, J =13.24, 7.34, 3.26 Hz, 2H) 5.17 (br. s., 1H) 7.13 (d, J = 8.53 Hz, 2H)7.37 (d, J = 8.53 Hz, 2H) 7.83 (d, J = 3.26 Hz, 1H) 7.91 (s, 1H) 52 (400MHz, DMSO-d6) δ ppm: 1.43-1.55 (m, 1H) 1.86 (br. s., 2H) 3.38-3.43 (m,2H) 3.81 (s, 3H) 3.89 (br. s., 2H) 4.94-5.02 (m, J = 7.94, 7.94, 3.95,3.76 Hz, 1H) 6.21 (d, J = 5.52 Hz, 1H) 7.27 (br. s., 1H) 7.33 (d, J =8.53 Hz, 1H) 7.73-7.82 (m, 2H) 7.92 (d, J = 3.51 Hz, 1H) 8.24 (d, J =5.52 Hz, 1H) 53 (400 MHz, DMSO-d6) δ ppm: 1.52-1.64 (m, J = 12.33, 8.20,8.20, 3.89 Hz, 2H) 1.89-2.00 (m, 2H) 3.35-3.45 (m, 1H) 3.79 (s, 3H) 3.85(br. s., 2H) 5.03 (ddd, J = 7.72, 4.14, 3.95 Hz, 1H) 6.61 (d, J = 6.27Hz, 1H) 7.23 (s, 2H) 7.28 (d, J = 8.53 Hz, 1H) 7.66 (d, J = 2.01 Hz, 1H)7.71 (dd, J = 8.53, 2.01 Hz, 1H) 7.93 (t, 1H) 54 (400 MHz, CDCl₃) δ ppm:1.78-1.88 (m, 2H) 1.90-2.00 (m, 2H) 3.53-3.93 (m, 7H) 4.95-5.10 (m, 3H)6.68 (d, J = 7.82 Hz, 1H) 6.77-6.84 (m, 2H) 6.87-6.92 (m, 2H) 6.99-7.06(m, 1H) 7.17-7.21 (m, 1H) 7.28 (d, J = 6.45 Hz, 1H) 7.82 (d, J = 2.34Hz, 1H) 55 (400 MHz, MeOD-d4) δ ppm: 1.77-1.86 (m, 2H) 2.02-2.10 (m, 2H)3.16 (t, J = 8.21 Hz, 2H) 3.71 (br. s., 2H) 4.04 (br. s., 2H) 4.12 (t,2H) 5.16-5.23 (m, 1H) 7.01-7.13 (m, 2H) 7.20-7.30 (m, 2H) 7.82 (d, J =3.32 Hz, 1H) 8.16 (d, J = 8.01 Hz, 1H) 8.53 (s, 1H) 56 (400 MHz,MeOD-d4) δ ppm: 1.80-1.89 (m, 2H) 2.04-2.12 (m, 2H) 3.20 (t, 2H)3.47-3.54 (m, 2H) 3.80-3.87 (m, 2H) 4.45-4.49 (m, 2H) 4.93 (m, 1H)5.10-5.16 (m, 1H) 7.04-7.09 (m, 1H) 7.16-7.21 (m, 1H) 7.26 (d, J = 7.62Hz, 1H) 7.82 (d, J = 3.52 Hz, 1H) 7.95 (s, 1H) 57 (400 MHz, MeOD) δ ppm:1.78-1.86 (m, 2H) 2.03-2.10 (m, 2H) 2.41 (s, 3H) 2.57 (t, 2H) 2.65 (t,2H) 3.51 (t, 2H) 3.70 (br. s., 2H) 3.79 (t, 2H) 4.03 (br. s., 2H) 5.20(dd, J = 10.79, 3.51 Hz, 1H) 6.94 (s, 1H) 7.84 (d, J = 3.51 Hz, 1H) 8.49(s, 1H) 58 (400 MHz, CDCl₃) δ ppm: 1.16 (none, 1H) 1.63-1.72 (m, 1H)1.75-1.84 (m, 1H) 1.98-2.05 (m, 1H) 2.11-2.19 (m, 1H) 3.10-3.18 (m, J =13.60, 3.60, 3.60, 3.42 Hz, 1H) 3.41-3.49 (m, 1H) 3.83-3.95 (m, 1H)4.12-4.24 (m, 1H) 5.11-5.17 (m, 1H) 5.21-5.28 (m, 2H) 7.40-7.53 (m, 4H)7.80-7.88 (m, 4H) 59 (300 MHz, MeOH) δ ppm: 1.69-1.88 (m, 2H) 1.93-2.10(m, 1H) 1.93-2.10 (m, 1H) 3.46-3.62 (m, 2H) 3.73-3.89 (m, 1H) 3.73-3.89(m, 1H) 4.83 (s, 2H) 5.10-5.18 (m, 1H) 6.96 (d, J = 8.96 Hz, 2H) 7.27(d, J = 8.96 Hz, 2H) 7.82 (d, J = 3.24 Hz, 1H) 60 (300 MHz, MeOH) δ ppm:1.87-1.98 (m, 2H) 2.06-2.15 (m, 2H) 2.58 (t, J = 8.30 Hz, 2H) 2.87-2.95(m, 2H) 3.23 (s, 2H) 3.79 (s, 3H) 4.96-5.02 (m, 1H) 6.91 (d, J = 8.77Hz, 2H) 7.48 (d, J = 8.77 Hz, 2H) 7.83 (d, J = 3.43 Hz, 1H) 61 (300 MHz,MeOH) δ ppm: 1.88 (td, J = 8.15, 4.29 Hz, 2H) 2.08 (td, J = 7.77, 3.34Hz, 2H) 2.55 (t, J = 9.16 Hz, 2H) 2.86-2.96 (m, 2H) 3.22 (t, J = 8.39Hz, 2H) 3.38 (s, 2H) 4.20 (t, J = 8.39 Hz, 2H) 4.96 (d, J = 4.01 Hz, 1H)7.05 (t, 1H) 7.17 (t, J = 7.82 Hz, 1H) 7.25 (d, J = 7.44 Hz, 1H) 7.82(d, J = 3.24 Hz, 1H) 8.15 (d, J = 8.01 Hz, 1H) 62 (300 MHz, MeOH) δ ppm:1.81-1.98 (m, 2H) 2.02-2.15 (m, 2H) 2.52 (t, 1H) 2.79-2.92 (m, 2H) 3.18(s, 2H) 4.96-5.04 (m, 1H) 6.71-6.79 (m, 1H) 7.00 (d, 1H) 7.13 (t, J =7.34 Hz, 1H) 7.27-7.44 (m, 5H) 7.82 (d, J = 3.43 Hz, 1H) 63 (300 MHz,MeOH) δ ppm: 1.83-2.01 (m, 2H) 2.03-2.20 (m, 2H) 3.47 (ddd, J = 11.21,7.10, 6.87 Hz, 1H) 3.66 (ddd, J = 17.36, 3.72, 3.53 Hz, 2H) 3.86 (ddd, J= 17.40, 3.86, 3.72 Hz, 1H) 4.24 (s, 2H) 4.62 (s, 2H) 5.42 (dt, J =7.01, 3.46 Hz, 1H) 7.40-7.48 (m, 2H) 7.63 (s, 1H) 7.85-7.97 (m, 2H) 8.22(d, J = 4.96 Hz, 1H) 64 (300 MHz, MeOH) δ ppm: 1.79-2.03 (m, 2H)2.04-2.27 (m, 2H) 3.52-3.75 (m, 1H) 3.75-3.96 (m, 2H) 4.12 (s, 2H)5.35-5.48 (m, 1H) 6.66 (dd, J = 8.30, 1.24 Hz, 1H) 6.82 (dd, J = 8.01,1.14 Hz, 1H) 7.13 (t, J = 8.20 Hz, 1H) 8.19 (dd, J = 4.67, 2.96 Hz, 1H)65 (300 MHz, DMSO-d6) δ ppm: 1.71 (br. s., 2H) 1.92 (br. s., 2H) 2.33(br. s., 2H) 2.69 (br. s., 2H) 2.99 (br. s., 2H) 3.08-3.20 (m, J = 7.32,7.32, 7.20, 4.48 Hz, 1H) 3.56-3.69 (m, J = 13.04, 6.46, 6.34, 4.29 Hz,1H) 4.30 (d, J = 6.29 Hz, 2H) 4.79 (td, J = 7.49, 3.72 Hz, 1H) 7.17-7.36(m, 7H) 7.91 (d, J = 3.24 Hz, 1H) 8.32 (br. s., 1H) 66 (400 MHz, MeOD) δppm: 1.78-1.91 (m, 2H) 1.96-2.10 (m, 2H) 2.41 (t, J = 7.20 Hz, 2H) 2.59(t, 1H) 2.83 (br. s., 2H) 4.01 (t, J = 6.06 Hz, 2H) 4.95 (dt, J = 7.52,3.69 Hz, 1H) 6.90 (dd, 1H) 7.00 (t, J = 8.72 Hz, 2H) 7.82 (d, J = 3.28Hz, 1H) 67 (400 MHz, MeOD-d4) δ ppm: 1.76-1.86 (m, 2H) 2.02-2.11 (m, 2H)3.63-3.72 (m, 2H) 4.01-4.10 (m, 2H) 5.16-5.22 (m, 1H) 7.31 (d, J = 0.98Hz, 1H) 7.43 (d, J = 7.23 Hz, 1H) 7.51-7.61 (m, J = 14.92, 7.43, 7.43,7.43, 1.07 Hz, 2H) 7.76 (dd, J = 7.42, 0.78 Hz, 1H) 7.83 (d, J = 3.52Hz, 1H) 8.31 (d, J = 1.17 Hz, 1H) 68 (400 MHz, MeOD-d4) δ ppm: 1.73-1.83(m, 2H) 1.98-2.07 (m, 2H) 3.68-3.77 (m, 2H) 3.81 (s, 3H) 4.01-4.09 (m,2H) 5.07-5.14 (m, 1H) 6.94-7.00 (m, 2H) 7.74 (d, J = 3.52 Hz, 1H)7.76-7.81 (m, 2H) 8.26 (d, J = 2.93 Hz, 1H) 69 (400 MHz, MeOD-d4) δ ppm:1.78-1.89 (m, 2H) 2.02-2.12 (m, 2H) 3.67-3.78 (m, 2H) 3.83 (s, 3H)3.99-4.11 (m, 2H) 5.17-5.24 (m, 1H) 6.74 (dd, J = 13.09, 2.34 Hz, 1H)6.85 (dd, J = 8.89, 2.25 Hz, 1H) 7.14 (s, 1H) 7.58 (t, J = 8.79 Hz, 1H)7.83 (d, J = 3.52 Hz, 1H) 8.42 (s, 1H) 70 (400 MHz, MeOD-d4) δ ppm:1.77-1.87 (m, 2H) 2.04-2.11 (m, 2H) 3.65-3.75 (m, 2H) 3.80 (s, 3H)4.01-4.11 (m, 2H) 5.16-5.23 (m, 1H) 6.47 (d, J = 46.70 Hz, 1H) 6.74 (t,J = 2.34 Hz, 1H) 6.76 (s, 1H) 7.03 (s, 1H) 7.16-7.22 (m, 1H) 7.83 (d, J= 3.52 Hz, 1H) 8.36 (s, 1H) 71 (400 MHz, MeOD-d4) δ ppm: 1.75-1.85 (m,2H) 2.02-2.10 (m, 2H) 3.61-3.70 (m, 2H) 3.76 (s, 3H) 3.99-4.08 (m, 2H)5.18 (d, J = 3.13 Hz, 1H) 5.49 (s, 1H) 6.85-6.89 (m, 2H) 7.05 (s, 1H)7.27-7.32 (m, 2H) 7.83 (d, J = 3.32 Hz, 1H) 8.32 (d, J = 0.98 Hz, 1H) 72(400 MHz, MeOD-d4) δ ppm: 1.76-1.85 (m, 2H) 2.03-2.10 (m, 2H) 3.62-3.70(m, 2H) 3.77 (s, 3H) 4.00-4.08 (m, 2H) 5.16-5.22 (m, 1H) 5.79 (s, 1H)6.66-6.72 (m, 2H) 7.07 (s, 1H) 7.17 (t, J = 8.60 Hz, 1H) 7.83 (d, J =3.52 Hz, 1H) 8.32 (d, J = 0.98 Hz, 1H) 73 (400 MHz, DMSO-d6) δ ppm:1.57-1.66 (m, 4H) 1.94-2.02 (m, 4H) 3.45-3.54 (m, 4H) 3.76 (s, 6H)3.93-4.02 (m, 4H) 5.02-5.08 (m, 2H) 6.91-6.95 (m, 4H) 7.07 (d, J = 1.17Hz, 2H) 7.25 (br. s., 4H) 7.32-7.36 (m, 4H) 7.92 (d, J = 3.32 Hz, 2H)8.41 (d, J = 0.98 Hz, 2H) 11.68 (s, 2H) 74 (400 MHz, MeOD-d4) δ ppm:1.76-1.86 (m, 6H) 2.03-2.10 (m, 6H) 3.62-3.72 (m, 6H) 3.80 (s, 6H) 3.83(s, 3H) 3.90 (s, 6H) 3.99 (s, 3H) 3.99-4.09 (m, 6H) 5.15-5.21 (m, 3H)6.79 (d, 3H) 6.88-6.97 (m, 6H) 7.37-7.45 (m, 6H) 7.82 (d, 3H) 8.40 (d,1H) 8.51 (d, 2H) 75 (300 MHz, MeOH) δ ppm: 1.68-1.80 (m, 2H) 1.90-2.06(m, 2H) 3.08-3.12 (m, 1H) 3.28-3.42 (m, 2H) 3.44-3.58 (m, 2H) 5.12-5.19(m, 1H) 6.05-6.08 (m, 1H) 7.23-7.28 (m, 1H) 7.41-7.48 (m, 2H) 7.50-7.58(m, 2H) 7.84 (d, J = 3.43 Hz, 1H) 7.96 (ddd, J = 8.01, 1.91, 1.72 Hz,1H) 8.06 (s, 1H) 8.46 (dd, J = 4.96, 1.53 Hz, 1H) 8.62-8.66 (m, 1H) 76(300 MHz, CDCl₃) δ ppm: 1.75-2.03 (m, 4H) 3.54 (d, J = 8.01 Hz, 1H) 3.73(s, 3H) 3.77-3.90 (m, 1H) 3.85 (dd, J = 9.54, 4.20 Hz, 1H) 5.00 (br. s.,2H) 5.07 (dd, J = 6.68, 3.43 Hz, 1H) 5.90 (s, 1H) 6.87-7.05 (m, 3H)7.20-7.39 (m, 5H) 7.82 (d, J = 2.48 Hz, 1H) 8.28 (s, 1H) 77 (400 MHz,MeOD-d4) δ ppm: 1.83 (br. s., 2H) 2.05 (d, J = 4.10 Hz, 2H) 3.48 (ddd, J= 13.33, 8.25, 3.42 Hz, 2H) 3.81 (br. s., 2H) 5.13 (br. s., 1H) 5.49 (s,1H) 5.69 (s, 1H) 7.18 (dd, J = 8.11, 1.07 Hz, 1H) 7.23 (td, J = 7.57,1.27 Hz, 1H) 7.33-7.40 (m, 1H) 7.68 (dd, J = 7.91, 1.47 Hz, 1H) 7.81 (d,J = 3.52 Hz, 1H) 8.24 (s, 1H) 78 (300 MHz, CDCl₃) δ ppm: 0.56-0.70 (m,2H) 0.89 (d, J = 6.87 Hz, 2H) 1.45-1.59 (m, 1H) 1.73-1.87 (m, 3H)1.87-2.02 (m, 2H) 3.39-3.55 (m, 2H) 3.78-3.92 (m, 2H) 4.98 (br. s., 2H)5.03-5.14 (m, 1H) 5.87 (s, 1H) 6.73 (s, 1H) 6.78-6.91 (m, 2H) 7.82 (d, J= 1.91 Hz, 1H) 8.24 (s, 1H) 79 (400 MHz, MeOD-d4) δ ppm: 1.76-1.89 (m,2H) 1.99-2.13 (m, J = 16.61, 3.81, 3.66, 3.66 Hz, 2H) 3.48 (br. s., 2H)3.87 (d, J = 9.77 Hz, 2H) 5.14 (br. s., 1H) 6.40 (d, J = 11.14 Hz, 1H)6.88 (d, J = 11.14 Hz, 1H) 7.14-7.30 (m, 3H) 7.31-7.41 (m, 1H) 7.81 (d,J = 3.52 Hz, 1H) 8.26 (s, 1H) 80 (300 MHz, MeOH) δ ppm: 1.78-1.94 (m,2H) 2.03-2.14 (m, 2H) 2.97-3.15 (m, 2H) 3.54-3.65 (m, 2H) 3.73 (s, 3H)4.91-5.05 (m, 1H) 6.85 (d, J = 2.86 Hz, 1H) 6.98 (d, J = 3.05 Hz, 1H)7.08 (d, J = 8.96 Hz, 1H) 7.66 (s, 1H) 7.73 (d, J = 3.24 Hz, 1H 81 (400MHz, MeOD) δ ppm: 1.69-1.78 (m, 2H) 1.97-2.05 (m, 2H) 2.47 (s, 6H) 2.96(t, J = 5.27 Hz, 2H) 3.55-3.62 (m, 2H) 3.98-4.05 (m, 2H) 4.10 (t, J =5.27 Hz, 2H) 5.08 (tt, J = 7.53, 3.76 Hz, 1H) 6.90-7.00 (m, 4H) 7.73 (d,J = 3.26 Hz, 1H) 7.79 (s, 1H) 82 (400 MHz, DMSO-d6) δ ppm: 1.44-1.75 (m,2H) 1.83-2.11 (m, 2H) 3.58 (s, 2H) 4.08 (s, 2H) 5.08 (s, 1H) 7.26 (s,2H) 7.40 (s, 2H) 7.54 (s, 1H) 7.87 (s, 1H) 7.93 (d, J = 3.32 Hz, 1H)7.99 (s, 1H) 8.40 (s, 1H) 8.50 (d, J = 1.17 Hz, 1H) 83 (400 MHz,MeOD-d4) δ ppm: 1.89 (br. s., 2H) 2.09 (br. s., 2H) 2.59 (s, 3H) 3.78(br. s., 2H) 4.04 (br. s., 2H) 5.17-5.23 (m, 1H) 7.34 (dd, J = 8.40,1.76 Hz, 1H) 7.41 (d, J = 1.95 Hz, 1H) 7.73 (d, J = 8.21 Hz, 1H) 7.82(d, J = 3.32 Hz, 1H) 8.10 (s, 1H) 84 (400 MHz, MeOD-d4) δ ppm: 1.77-1.86(m, 2H) 2.04-2.12 (m, 2H) 3.61-3.68 (m, 2H) 4.00-4.08 (m, 2H) 4.11 (s,3H) 4.61 (br. s., 1H) 5.16-5.22 (m, 1H) 7.14 (dd, J = 15.04, 0.98 Hz,1H) 7.24 (d, J = 8.40 Hz, 1H) 7.60 (dd, J = 8.40, 7.23 Hz, 1H) 7.74 (d,J = 0.98 Hz, 1H) 7.83 (d, J = 3.32 Hz, 1H) 8.11 (dd, J = 7.82, 1.76 Hz,1H) 8.28 (d, J = 0.98 Hz, 1H) 85 (400 MHz, MeOD) δ ppm: 1.70-1.79 (m,2H) 2.02 (ddd, J = 13.05, 3.76, 3.51 Hz, 2H) 2.36 (s, 6H) 3.61 (ddd, J =13.68, 4.14, 4.02 Hz, 2H) 3.68 (s, 2H) 3.75 (s, 3H) 4.03 (ddd, J =13.36, 7.34, 3.39 Hz, 2H) 5.09 (tt, J = 7.43, 3.73 Hz, 1H) 6.65 (dd, J =8.28, 2.26 Hz, 1H) 6.77 (d, J = 2.01 Hz, 1H) 7.23 (d, J = 8.28 Hz, 1H)7.73 (d, J = 3.26 Hz, 1H) 7.83 (s, 1H) 86 (300 MHz, MeOH) δ ppm:2.12-2.27 (m, 2H) 3.69-3.92 (m, 3H) 5.35-5.47 (m, 1H) 7.33 (td, J =3.81, 1.53 Hz, 1H) 7.68-7.87 (m, 2H) 7.68-7.87 (m, J = 18.48, 3.22,3.08, 3.08 Hz, 2H) 8.01 (d, J = 1.91 Hz, 1H) 7.95-8.09 (m, 1H) 8.55 (dd,J = 8.39, 5.15 Hz, 1H)

6.32. Cloning, Expression and Purification of Recombinant DeoxycytidineKinase

A full-length cDNA of deoxycytidine kinase was obtained by RT-PCR usingknown primers with human lymph node RNA (Clontech, Mountain View,Calif.) as template. This full length ORF was cloned into pCR4Blunt-Topo(Invitrogen, Carlsbad, Calif.). Protein expression and purification wasadapted from the procedure described by Sabini et al., Nature StructureBiology 10, 513-519 (2003).

Here, the full length ORF of deoxycytidine kinase was subcloned intopET28(a+) (Novagen, San Diego, Calif.) using endonucleases (Nde1 andXho1). The plasmid was transformed into a bacterial strain BL21 (DE3). Asingle colony was picked and grown in LB broth containing Kanamycin 50μg/ml and 2% glucose. Cells were grown at 37° C. until OD₆₀₀ was 0.6.Then, 0.1 mM IPTG was added and the culture incubated at 30° C. for 16hours. Cells were harvested by centrifugation and resuspended in 50 mlof 50 mM Tris, pH 8.0 containing 1 mg/ml of Lysozyme, 10% glycerol and10 mM MgCl₂, 50 μg/ml of DNase 1 and 1 tablet of Roche protein inhibitorcocktail and incubated on ice for 30 minutes. Cells were then disruptedon ice using a homogenizer. Whole cell lysate were cleared bycentrifugation at 20,000 rpm for 20 minutes. The supernatant was loadedonto a Ni-NTA Sepharose column (20 ml of bed volume) preequilibratedwith 50 mM Tris, pH 8.0, containing 10 mM MgCl₂, 10% glycerol. Thecolumn was washed with the same buffer containing 20 mM imidazole untilOD₂₈₀ reached the baseline at a flow rate of 2 ml/min. Deoxycytidinekinase was eluted with a gradient of 120 ml 0 to 800 mM imidazole in thesame buffer. The protein peak was pooled and dialyzed against 2 litersof 50 mM Tris, pH 7.5 containing 5 mM MgCl₂, 1 mM EDTA, 5 mM DTT and 20%glycerol. Protein aliquots were stored at −80° C. Protein was at least95% pure as estimated by the SDS-PAGE.

6.33. Deoxycytidine Kinase Filter Binding Assay

This filter binding assay is based on the binding of the deoxycytidinekinase reaction product dCMP to the positive charged DE-81 filter disk(Ives, D. H. and Wang S.-M., Methods Enzymol. 51:337-345 (1978)).Waterman DE-81 or Millipore DEAE 96 well plates were chosen as thebinding media for the assay.

Deoxycytidine kinase at a concentration of 5 to 50 nM was incubated with1 μM of ³H-labeled deoxycytidine (20 Ci/mmol) and 10 μM ATP in 50 μl of50 mM Tris, pH 7.6, containing 5 mM MgCl₂, 0.5 mM DTT, 0.1% pluronicacid and 1 mg/ml BSA for 5 to 40 minutes at room temperature. Ten μl of10 mM deoxycytidine was added and mixed. Ten to 20 μl of reactionsolution (per well) was loaded to a DE-81 96 well plate pre-wetted with1 mM ammonium formate, pH 3.6. The plate was washed three times with 1mM ammonium formate, pH 3.6 and dried. The plate bottom was sealed withthe plate seal and 100 μl of scintillation fluid was added per well and³H-labeled products were counted by a TOPcount scintillation counter.

6.34. Deoxycytidine Kinase Cell-Based Assay

A simple and sensitive cell based assay was developed based on the knownin vivo activation of cytosineb-D-arabinofuranoside (AraC) bydeoxycytidine kinase: inhibition of deoxycytidine kinase would reversethe cytotoxicity of AraC.

A human T lymphoblastoid cell line CCRF-CEM (ATCC: CCL119) was seeded in100 μl of a modified RPMI 1640 medium containing 30 nM AraC at 4,000cells/well. Different concentration of deoxycytidine kinase inhibitorswas added. The cells were grown at 37° C. for 3 days. Then, 100 μl ofCellTiter-Glo Luminescent Cell Viability Assay reagent (Promega) wasadded and incubated at room temperature for 60 minutes.Chemiluminescence was recorded using a Tecan luminescence reader. Theluminescence represents total ATP concentrations in the cells, which isproportional to cell number.

6.35. Thymidine and Uridine Kinase Inhibition Assays

Whole cell lysate made from CEM-CLL cells, as described above, were usedas enzyme source.

Whole cell lysate were incubated with 1 μM of 3H-labeled thymidine (20Ci/mmol) and 200 μM ATP in 50 μl of 50 mM Tris, pH 7.6, containing 5 mMMgCl₂, 0.5 mM DTT with or without compounds at various concentration for5 to 40 min at room temperature. Then 10 μl of 10 mM cold thymidine wasadded and mixed. 10 to 20 μl of reaction solution (per well) was loadedto a DE-81 96 well plate pre-wetted with 1 mM ammonium formate, pH 3.6.The plate was washed three times with 1 mM ammonium formate, pH 3.6, anddried. The plate bottom was sealed with the plate seal and 100 μl ofscintillation fluid was added per well, and ³H-labled products werecounted by a TOPcount scintillation counter.

For the uridine kinase inhibition assay, the procedure was the sameexcept the ATP concentration was increased to 400 μM.

6.36. Calculating IC₅₀ Values

The IC₅₀ of a compound with regard to a given target is determined byfitting the relevant data, using the Levenburg Marquardt algorithm, tothe equation:y=A+((B−A)/(1+((C/x)^D)))wherein A is the minimum y value; B is the maximum y value; C is theIC₅₀; and D is the slope. The calculation of the IC₅₀ is performed usingXLFit4 software (ID Business Solutions Inc., Bridgewater, N.J. 08807)for Microsoft Excel (the above equation is model 205 of that software).

6.37. Inhibition of Cancer Cell Growth

Cell proliferation evaluated by MTS assay was used to study the synergyof compounds of the invention and 4-hydroperoxycyclophosphamide (4-HC),which is an active form of cyclophosphamide in mouse B cell lymphomacells (BCL-1). BCL-1 cells were grown in RPMI 1640 growth medium with10% fetal bovine serum and 0.05 mM 2-mercaptoethanol at 37° C. in anincubator with 5% CO₂. When the cells reached confluence, they weretrypsinized, washed and counted. 12000 mL-1 cells were seeded intriplicate cultures into one well of 96 well plates and culturedovernight with 200 μl growth medium. On the second day, the compoundbeing tested, 4-HC, or a combinations of the two were added to the cellsand continued to incubate for 72 hours. Then, a MTS assay was performedfor these treated or control cells described as follows.

First, 100 μl of the culture medium from each well of the 96-well platewas carefully removed. Second, 20 μl of pre-warmed MTS reagent (Promega,cat. G3580) was added into each well (including the “blank” wells withno cells), mixed well, and immediately placed in a incubator at 37° C.Finally, 25 μl of 10% SDS was added in each well to stop the reactionafter incubated for one hour, and the absorbance for each well was readat 490 nm using a plate reader.

All the experiments were repeated at least three times with similarpattern of results. The combined effect of the compound begin tested and4-HC was determined by the combination index methodology described byChou, T.-C., and Talalay, P., Adv. Enz. Regul. 22:27-55 (1984).

The effect of different concentrations of a compound of the inventionalone and in combination with 4-HC on BCL-1 cell growth is shown inFIGS. 1-4.

All publications (e.g., patents and patent applications) cited above areincorporated herein by reference in their entireties.

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: L₁ is a bond,—C(O)—, —SO₂—, or —C(R₄)_(2—;) L₂ is a bond, —O—, —C(O)—, —SO₂—,—C(NOH)—, or —C(R₅)_(2—;) A₂ is optionally substituted cycloalkyl, arylor heterocycle; R₁ is hydrogen, halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OR₄,or optionally substituted alkyl; R₂ is hydrogen, halogen, —OH, —NH₂,—NO₂, —CN, —C(O)OR₄, or optionally substituted alkyl; each R₃ isindependently ═O or optionally substituted lower alkyl; each R₄ isindependently hydrogen or lower alkyl; each R₅ is independentlyhydrogen, fluoro, hydroxyl or lower alkyl, provided that when one of R₅is hydroxyl, the other is neither hydroxyl nor fluoro; each R₆ ishalogen, —OH, —NH₂, —NO₂, —CN, or optionally substituted alkyl; m is0-4; and p is 0-2.
 2. The compound of claim 1, which is of the formula:


3. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: L₁ is a bond,—C(O)—, —SO₂—, or —C(R₄)₂—; L₂ is a bond, —O—, —C(O)—, —SO₂—, —C(NOH)—,or —C(R₅)₂—; A₂ is optionally substituted cycloalkyl, aryl orheterocycle; R₁ is hydrogen, halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OR₄, oroptionally substituted alkyl; R₂ is hydrogen, halogen, —OH, —NH₂, —NO₂,—CN, —C(O)OR₄, or optionally substituted alkyl; each R₃ is independently═O or optionally substituted lower alkyl; each R₄ is independentlyhydrogen or lower alkyl; each R₅ is independently hydrogen, fluoro,hydroxyl or lower alkyl, provided that when one of R₅ is hydroxyl, theother is neither hydroxyl nor fluoro; each R₆ is halogen, —OH, —NH₂,—NO₂, —CN, or optionally substituted alkyl; m is 0-4; and q is 0-4. 4.The compound of claim 1 or 3, wherein A₂ is optionally substitutedphenyl, pyridine, quinoline, thiophene, indole, pyrazole, piperidine,morpholine, or pyrrolidine.
 5. The compound of claim 1 or 3, wherein L₂is —O—.
 6. The compound of claim 1 or 3, wherein L₂ is —C(O)— or—C(NOH)—.
 7. The compound of claim 1 or 3, wherein L₂ is —C(R₅)₂—.
 8. Acompound of the formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein: L₂ isa bond, —O—, —C(O)—, —SO₂—, —C(NOH)—, or —C(R₅)₂—; A₁ is optionallysubstituted cycloalkyl, aryl or heterocycle; R₁ is hydrogen, halogen,—OH, —NH₂, —NO₂, —CN, —C(O)OR₄, or optionally substituted alkyl; R₂ ishydrogen, halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OR₄, or optionallysubstituted alkyl; each R₃ is independently ═O or optionally substitutedlower alkyl; each R₄ is independently hydrogen or lower alkyl; each R₅is independently hydrogen, fluoro, hydroxyl or lower alkyl, providedthat when one of R₅ is hydroxyl, the other is neither hydroxyl norfluoro; each R₇ is halogen, —OR₈, —NH₂, —NO₂, —C(O)N(R₈)₂, —CN, oroptionally substituted alkyl, aryl or heterocycle; each R₈ is hydrogenor optionally substituted alkyl; n is 1-3; m is 0-3 if n is 1, m is 0-4if n is 2, or m is 0-5 if n is 3; and r is 0-5.
 9. The compound of claim8, wherein A₁ is optionally substituted imidazole, pyridine, pyrimidine,purine, triazine, or thiazole.
 10. The compound of claim 8, wherein R₇is —OR₈, C(O)N(R₈)₂, or —CN.
 11. The compound of claim 8, wherein R₇ isan optionally substituted non-aromatic heterocycle.
 12. The compound ofclaim 11, wherein the heterocycle is hexahydropyrimidine, morpholine,piperidine, pyrrolidine, or 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidine.13. The compound of claim 8, wherein L₂ is —O—.
 14. The compound ofclaim 8, wherein L₂ is —C(O)— or —C(NOH)—.
 15. The compound of claim 8,wherein L₂ is —C(R₅)₂—.
 16. The compound of claim 8, wherein R₁ ishalogen.
 17. The compound of claim 8, wherein R₂ is hydrogen.
 18. Acomposition comprising a compound of claim 1, 3, or 8 and apharmaceutically acceptable excipient or diluent.